Process Intensification on Rotating Surfaces Controlling Chemical Reactivity and Selectivity

Process intensification on rotating surfaces controlling chemical reactivity and selectivity

LYZU YASMIN

MSc

This Thesis is presented for the degree of Doctor of Philosophy at the University of Western Australia

School of Chemistry and Biochemistry

2014

Abstract

A rotating microfluidic device namely, the vortex fluidic device (VFD) as a form of process intensification, has been optimised and applied in different organic syntheses. This device allows for the synthesis of molecules that are not usually accessible or are only accessible with limited practical convenience using conventional methods. The low cost VFD, which has a rapidly rotating tube open at one end, forms dynamic thin films at a high rotating speed. Dual operation modes, controlled residence times and variable parameters of this device make it very effective and efficient for different types of organic syntheses. In the ‘confined mode’ of operation, intense shear is generated in the resulting thin films for finite sub-millilitre volumes of liquid, depending on the speed, tilt angle of the tube, and other operating parameters of the VFD. It can also operate under the ‘continuous flow mode’ with jet feeds delivering liquids into the rotating tube where additional shear is generated in the thin films from the viscous drag as the liquid whirls along the tube. Diels-Alder dimerisations of cyclopentadiene and methyl cyclopentadiene were used as model reactions for optimising the operational parameters of the VFD. The results of the optimised conditions of the dimerisation reactions have been translated into other organic reactions. Generally the results establish that dramatic control of reactivity and selectivity can be achieved using the VFD, which highlights the versatility of this device.

Amino functionalized 2,4,6-triarylpyridines were deemed as important precursors for G-quadruplex DNA binding ligands. A synthetic route to access these compounds under continuous flow (through 1,5-diketone precursor) has been developed in the VFD, overcoming a series of competing reactions and effectively controlling chemical reactivity and selectivity. This device also overcomes the multiple passes involved in using the spinning disc processor (SDP) due to the longer residence time that is able to be achieved relative to the SDP. The one pot reaction of amino-functionalized 2,4,6- triarylpyridines has also been established using the continuous flow mode of the VFD in a single pass, in the presence of ammonium acetate and PEG. A synthetic route to access chalcones has also been developed by changing both, the parameters of the VFD and the ratio of the starting materials used.

A facile, one pot method for the synthesis of polysubstituted pyridines and N,N´- dimethyl containing 2,4,6-triarylpyridines with high functionality has been established in the presence of ammonium acetate and PEG as a reaction medium using the VFD. The choice of the VFD in this study relates to its ability to scale down under constant shear using the confined mode, in further mapping out the novel capabilities of the microfluidic platform in general, as well the potential to develop a robust benign method for a diverse range of molecules with fluorescence capabilities. Analysis of the UV-Vis and fluorescence spectra of these pyridines was investigated and the results were promising.

Furthermore, a novel and convenient method has been developed for the synthesis of different resorcin[4]arenes and pyrogallol[4]arenes as the C4v isomer using the VFD under continuous flow. The type of isomers formed was controlled by varying the parameters of the VFD, with an added advantage of significantly reduced reaction times and the amount of catalyst required. Also preformed C2h isomers were converted to C4v isomers in the VFD operating in the confined mode.

Finally, an efficient and green method has been established to promote Diels-Alder reactions without the use of a catalyst using the confined mode of the VFD. An aqueous solution with a low mole fraction of alcohol was used as a reaction medium and the Diels-Alder cycloadducts produced were in high yields from different 9-substitiuted anthracene and N-maleimide starting materials.

Overall, a major theme throughout the studies presented here is the use of green chemical strategies incorporating a microfluidic device, minimal catalysis, aqueous media and the use of alternative reaction mediums.

Table of Contents

Abstract ...... i Table of Contents...... iii List of Figures ...... vi List of Scheme...... vii Abbreviations...... viii Acknowledgements ...... x Details of Publications and Abstracts ...... xi Statement of candidate contribution...... xiii

1. Introduction ...... 1

1.1 Overview...... 1 1.2 Process Intensification ...... 1 1.2.1. Microfluidic rotating devices ...... 3 1.2.2. Microfluidic devices as green technology ...... 8 1.3 Triaryl and polysubstituted pyridines ...... 9 1.3.1 Application and structure ...... 9 1.3.2 Central ring assembly synthesis of trisubstituted pyridines ...... 11 1.3.2.1 Krohnke condensation reaction ...... 11 1.3.2.2 Improved Chichibabin reaction ...... 12 1.3.2.3 Potts method ...... 13 1.3.2.4 Solvent-free grinding reactions ...... 13 1.3.2.5 Using PEG as a reaction medium ...... 15 1.3.2.6 Using microfluidic device ...... 18 1.3.2.7 Using microwave reactor and catalyst ...... 19 1.4. Calix[4]arenes ...... 20 1.4.1 History of Calix[4]arenes ...... 20 1.4.2 Application of calix[4]arenes ...... 21 1.4.3 Stereochemistry of calix[4]arenes ...... 22 1.4.4 The mechanism of calix[4]arene condensation ...... 23 1.4.5 Synthesis of calix[4]arenes...... 24 1.4.5.1 Resorcinol-Aldehyde condensations ...... 24

iii

1.4.5.2 Other types of condensation reactions ...... 25 1.5 The Diels-Alder reaction ...... 28 1.5.1 History ...... 29 1.5.2 Acceleration and selectivity enhancement of Diels-Alder reaction .... 30 1.5.2.1 High pressure acceleration ...... 30 1.5.2.2 Using Lewis acid catalysis ...... 31 1.5.2.3 The effects of water on Diels-Alder reactions ...... 32 1.5.2.3.1 The effect of water on the rate of Diels-Alder reactions ...... 32 1.5.2.3.2 The effect of water on the selectivity of Diels–Alder reactions .... 33 1.5.2.3.3 The effect of additives on the rate and selectivity of Diels-Alder reactions in water ...... 34 1.5.2.4 Using supramolecular catalysis ...... 35 1.6 Challenges...... 36

2. Introduction to series of papers ...... 38

2.1. Optimization of Vortex fluidic device (VFD) ...... 38 2.2 Microfluidic synthesis of 2,4,6-triaryl and polysubstiuted pyridines ...... 40 2.3 Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes ...... 43 2.4 Diels-Alder reactions in aqueous medium ...... 45

3. Series of Papers ...... 47

3.1 Optimising a vortex fluidic device for controlling chemical reactivity and selectivity ...... 47 3.2 Thin film microfluidic synthesis of fluorescent highly substituted pyridines . 54 3.3 Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films ...... 59 3.4 Vortex fluidic promoted Diels-Alder reactions in aqueous medium ...... 63

4. Conclusions and future work...... 67 5. Online Support Information for Published Articles ...... 71

5.1 Supporting information for “Optimising a vortex fluidic device for controlling chemical reactivity and selectivity” ...... 71 5.2 Supporting information for “Thin film microfluidic synthesis of fluorescent highly substituted pyridines” ...... 81

5.3 Supporting information for “Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films” ...... 98 5.4 Supporting information for “Vortex fluidic promoted Diels-Alder reactions in aqueous medium” ...... 104

6. References ...... 108

List of Figures

Figure 1.1 Process intensification classification...... 2

Figure 1.2 Features of the spinning disc processor (SDP)...... 3

Figure 1.3 Illustration of the Rotating tube processor (RTP)...... 6

Figure 1.4 Schematic of the Vortex fluidic device (VFD)...... 7

Figure 1.5 Vortex fluidic device (VFD)...... 8

Figure 1.6 Representative structures of (i) 2,2´:6´,2´´-terpyridine, (ii) 4´-aryl-

2,2´:6´,2´´-terpyridine (iii) 2,4,6-triarylpyridine and (iv) polysubstituted pyridine...... 10

Figure 1.7 Cyclohexyl product...... 14

Figure 1.8 Structure of calix[4]resorcinarene molecule...... 21

Figure 1.9 Conformations of calix[4]arene...... 22

Figure 1.10 Relative configurations of calix[4]arene...... 23

Figure 1.11 HOMO-LUMO arrangements for Lewis acid catalysed (broken line) and uncatalyzed (solid line) Diels-Alder reactions with normal electron demand...... 31

Figure 1.12 Organopalladium cages...... 35

List of Schemes

Scheme 1.1 Krohnke condensation synthesis of trisubstituted pyridines...... 12

Scheme 1.2 Modified Chichibabin reaction for synthesis of triarylpyridines...... 12

Scheme 1.3 Potts method for the synthesis of trisubstituted pyridines...... 13

Scheme 1.4 Solvent-free grinding procedure for the synthesis of unsymmetrical triarylpyridine...... 14

Scheme 1.5 PEG method for the synthesis of symmetrical 4′-(pyridyl)-terpyridine. .... 16

Scheme 1.6 Procedure for the synthesis of 4´-aryl-2,6-bis(4-aminophenyl)pyridines. .. 16

Scheme 1.7 PEG method for the synthesis of symmetrical 4´-aryl-2,6-bis(4- aminophenyl)pyridines...... 17

Scheme 1.8 Synthesis of the dimethyl amino functionalized 4´-aryl-2,6-bis(4- aminophenyl)pyridines using a microfluidic platform...... 18

Scheme 1.9 Microwave irradiation (MWI) synthesis of polysubstituted pyridine...... 20

Scheme 1.10 The reaction of cyclocondensation of calix[4]arene...... 24

Scheme 1.11 Synthesis of calix[4]arene, 39 using Boron trifluoride...... 25

Scheme 1.12 Synthesis of calix[4]arene, 40 under Lewis acid catalyst...... 26

Scheme 1.13 Synthesis of calix[4]arene, 41 under BrØnsted acid catalyst...... 26

Scheme 1.14 Synthesis of octahydroxypyridine[4]arene, 42...... 27

Scheme 1.15 Synthesis of calix[4]arene, 43 using scandium(III) triflate...... 27

Scheme 1.16 Synthesis of calix[4]arene, 45 using lanthanide(III) tosylates...... 28

Scheme 1.17 Synthesis of pyrogallol[4]arene, 46 under microwave irradiation...... 28

Scheme 1.18 Schematic representation of the Diels-Alder reaction...... 29

Scheme 1.19 Diels-Alder reaction at high pressure...... 30

Scheme 2.1 Synthesis of 2,4,6-triarylpyridienes ...... 41

vii

Abbreviations

Ac Acetyl

API Atmospheric Pressure Ionization

Ar Aryl

Ced cohesive energy density

CpH Cyclopentadiene

DMSO Dimethylsulfoxide

DNA Deoxiribo Nucleic Acid

Et Ethyl

FMO Frontier Molecular Orbital

h-BN hexagonal - Boron Nitride

HOMO Highest Occupied Molecular Orbital

HR-MS High Resolution-Mass Spectroscopy

LUMO Lowest Unoccupied Molecular Orbital

Me Methyl

MeCN Acetonitrile

MeCpH Methylcyclopentadiene

Mp melting point

MS Mass Spectroscopy

MWI Microwave Irradiation

NASA National Aeronautics and Space Administration

NMR Nuclear Magnetic Resonance

PEG Polyethylene Glycol

Ph Phenyl

PI Process Intensification

PIRS Process Intensification on Rotating Surface

viii

PPA Polyphosphoric Acid ppm parts per million

RTP Rotating Tube processor

SDP Spinning Disc processor

STT Spinning Tube in Tube

TAP Triaryl Pyridine

TLC Thin Layer Chromatography

UV-vis Ultra Violet-visible

VFD Vortex Fluidic Device

XRD X-Ray Diffraction eqv equivalents

Acknowledgements

First and foremost, I would like to express my gratitude to the Almighty for blessing me with the determination, wisdom and health to complete this thesis. It was also not possible without the support, patience and guidance of several people. I would like to express my deepest gratitude to all of them.

I am extremely grateful to my supervisors Professor Colin Raston and Dr. Keith Stubbs for their time, scholarly inputs, directions and consistent encouragement throughout the research work. They made my journey dynamic, motivating and productive.

I would like to thank the staffs from the School of Chemistry and Biochemistry for their all-out assistance. Nevertheless, I should mention few names such as Dr. Lindsay Byrne for helping me with NMR, Dr. Brian Skelton for the assistance with XRD test, Dr. Anthony Reeder for helping with LC-MS and Mr. Damien Bainbridge for his kind help to resolve mechanical problems of VFD machine. I would also like to thank Trovis Coyle for helping me to run few of my compounds in LC-MS.

I would like to thank Dr. Paul Eggers for his help and guidance regarding fluorescence spectroscopy work. My gratitude must also go to all of the members in the Raston research group. I had a wonderful and interesting time as part of the group.

I must acknowledge and thank the University of Western Australia, Australian Research Council and Professor Colin Raston for granting me the APA (I) scholarship and other financial supports to accomplish the research.

I would like to extend special thanks to my Mom, sisters, brother and my Parent in laws. They were always encouraging me and supporting me with their best wishes. Last but definitely not least, I am very much indebted to my family, my loving, encouraging, and patient husband Atiq, my daughter Sharaba and my son Aarish who supported me always to see the achievement.

Details of Publications and Abstracts

Referred Journal Articles

1. L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston. Optimising a vortex fluidic device for controlling chemical reactivity and selectivity. Scientific Reports, 2013, 3, 2282.

Author Contributions: LY, CLR and KAS designed the organic synthesis experiments; LY performed the all chemical reactions and XC carried out fluid flow experiments; CLR designed the microfluidic platform; CLR, LY, KAS and XC finalised the manuscript.

(Overall contribution by LY: 70%)

2. L. Yasmin, P. K. Eggers, B.W. Skelton, K. A. Stubbs and C. L. Raston. Thin film microfluidic synthesis of fluorescent highly substituted pyridines. Green Chemistry, 2014, 16, 3450-3453.

Author Contributions: LY, PKE and KAS designed the research; LY performed the research; BWS carried out the crystallography; LY, KAS, CLR and PKE finalised the manuscript.

(Overall contribution by LY: 80%)

3. L. Yasmin, T. Coyle, K. A. Stubbs and C. L. Raston. Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films. Chemical Communications, 2013, 49, 10932-10934.

Author Contributions: LY, CLR and KAS designed the research; LY performed the research; TC performed the MS; LY, CLR and KAS finalised the manuscript.

(Overall contribution by LY: 80%)

4. L. Yasmin, K. A. Stubbs and C. L. Raston. Vortex fluidic promoted Diels-Alder reactions in aqueous medium. Tetrahedron Letters, 2014, 55(14), 2246-2248.

Author Contributions: LY, CLR and KAS designed the research; LY performed the research; LY, CLR and KAS finalised the manuscript.

(Overall contribution by LY: 85%)

Conference Abstracts

5. L. Yasmin, C. L. Raston, K. A. Stubbs and N. Smith. Process Intensification on rotating surfaces (PIRS) in controlling chemical reactivity and selectivity. Royal Australian Chemical Institute (RACI) National Convention, Melbourne, Victoria, Australia. 4-8th July, 2010. (Oral presentation).

6. L. Yasmin, K. A. Stubbs and C. L. Raston. Vortex fluidics in organic syntheses. Royal Australian Chemical Institute (RACI) WA Branch: Synthetic and Organic Chemistry Group One Day Symposium, University of Western Australia, Perth, Western Australia, Australia. 2nd December, 2011. (Oral presentation).

xii

Statement of candidate contribution

This Thesis contains the results of work carried out by the author in the Discipline of Chemistry, School of Chemistry and Biochemistry at The University of Western Australia during the Period July 2009 to July 2014.

The work presented herein contains no materials which the author has submitted or accepted for the award of another degree or diploma at any University and to the best of the author’s knowledge and belief, contains no material previously published or written by another person, except where due reference is made in the text.

Lyzu Yasmin

July 2014

xiii

Chapter 1 Introduction 1. Introduction

1.1 Overview

The method of process intensification has been used in this research in order to synthesize organic compounds such as triarylpyridines, calix[4]arenes and perform the Diels-Alder reactions in a very effictive way utilising a microfluidic device. This research also incorporates an overarching theme of green chemistry. All of these topics will be discussed briefly in the following chapters.

1.2 Process Intensification

Currently process intensification (PI) is one of the most significant and wide trends in chemical engineering and process technology. This technology has ability to match current and future challenges of the chemical and bio-based industry. The key challenges are, i) execution of more sustainable production processes, ii) adjustment to quick changing markets and iii) prospective to produce new innovative products for surviving global contest.1

Initially PI has focused on four areas; using centrifugal forces, compacting heat transfers, intensive mixing and combining technologies.2 Nowadays, PI is gaining more attention in designing new plants and retrofitting existing ones, as one of the main aims. It can reduce equipment size, improve yield, minimizing feedstock, etc. In addition, process intensification improves safety during the development of products which cannot be safely or successfully generated because of high reaction rates, violent exothermic reactions, or too hazardous reactants.2

The broad definition of PI was proposed by Stankiewicz and Moulijn3 as, “Any chemical engineering development that leads to a substantially smaller, cleaner and more energy efficient technology”. From this definition, it can be said that PI is attuned with many of the changes that need to be required in modern chemical processing plant design.4 These vital changes include reducing capital investment and energy use, enhancing process safety and flexibility and improving quality and environmental performance. Notably, these new chemical processing requirements are also attuned with the main theme of green chemistry.4 Based on this above definition, PI is classified

Chapter 1 Introduction into two classes: equipment and methods (Figure 1.1). The equipment class includes reactors and equipment for non-reactive operations. While, the methods class incorporates multi-functional reactors, hybrid separators, alternative energy resources and a category for any other methods used.3

The use of rotation is one of the best ways to intensify heat and mass transfer. Centrifugal forces are included with rotation to produce thin films. The rotating boiler was one of the earliest uses of a rotating system developed in Germany and those developed by NASA in order to overcome the adverse effect of zero gravity.4

Figure 1.1 Process intensification classification. Taken from the Reference 3.

Many different types of PI have been developed that depend on rotation for increasing mass and heat transfer, such as the rotating packed-bed reactor, the spinning disc processor (SDP), the rotating tube processor (RTP), the vortex flow reactor, the narrow channel processor and the spinning tube in tube (STT) reactor.5 The use of traditional batch processing is limited by anisotropic thermal environments and/or poor mass and heat transfer. Continuous flow PI strategies can overcome these limitations by proper mixing of products. Furthermore, this method has a lower capital cost as well as small processing footmark that can aid in the translation from small scale research production to industrial production. Minimum waste and low energy usage make PI strategies inherently safer. All components in PI are treated in the same way and can allow for the synthesis of compounds which are not usually easy to get or are only available with limited practical convenience in batch processing.6 2

Chapter 1 Introduction 1.2.1. Microfluidic rotating devices

A. Spinning Disc processor (SDP)

The spinning disc processor (SDP) was developed by Ramshaw’s group at the University of Newcastle (Newcastle, U.K.). Initially it was aimed at very fast liquid/liquid reactions with large heat effects, such as nitrations, sulfonations, and polymerizations. In recent years, the spinning disk processor (SDP) was brought forward as an alternative to traditional batch processing technology,7,8 claiming to offer distinct advantages with respect to mixing characteristics, heat and mass transfer and residence time distribution. An SDP is a simple and compact piece of equipment that consists of two gear pumps and a 10 cm diameter rotating disc (Figure 1.2). The spinning disc technology uses centrifugal accelerations to generate thin highly sheared films on rotating surfaces (10 to 3000 rpm). The salient features of the SDP include viscous drag that induces a high degree of turbulent mixing within these centrifugally motivated films. This leads to rapid interleaving and diffusion of reactant solutions and fast kinetics. The system is under plug flow conditions and thus, reactions can be highly chemo-selective. There are two or more possible reaction sites for the organic substrate. The SDP has feed jets directed close to the centre of a rapidly rotating disc where there is intense micro-mixing. The residence time of SDP is typically less than a second but this depends on the size of the disc, surface texture of the disc itself, viscosity and flow rates.9 It also has high heat and mass transfer10-12 and controlled residence time. Currently the SDP is being commercialized.

Figure 1.2 Features of the spinning disc processor (SDP). Taken from the Reference 12.

Chapter 1 Introduction A qualitative measure of the mixing efficiency in the liquid film can be obtained by calculation of the shear stress, , which is imposed on the liquid film by the rotational force as it moves over the disc surface. Shear stress is primarily caused by friction between fluid particles, due to fluid viscosity. The thin film produced on the disc is subjected to very high shear stress, promoting very high heat transfer rates between the film and the disc and high mass transfer rates between the liquid streams or between the film and the surrounding atmosphere. Having a high shear stress allows the mixing to be more efficient. The mixing intensity and liquid residence time (tres) have a dominating influence on the degree of conversion on the disc for chemical reactions. The shear stress ( can be defined13 as

……………………………………(1)

Where, η is dynamic viscosity, Qv is volumetric feed rate, vrel is mean film velocity, δ is film thickness, ω is angular velocity, ρ is density and r is disc radious.

From equation (1) it is clear that the angular velocity, ω, depends on the shear stress of the thin film and thus, by the rotational speed of the disc (N):

………………………………………………….(2)

Where, N is rotational speed of the disc.

Hence, the mixing characteristics on the disc improve with increasing spin rate. This is strictly applicable for laminar flow only (Reynolds number, Re <4) and does not take into account the increasing mixing efficiency by turbulent film flow (Re > 20).13

Equation 3 indicates that residence time, tres on the disc is inversely proportional to angular velocity, ω:

…………………..(3)

Where, ro is radious at exit from the disc and ri is radial distance of inlet tube from the center of the disc. 4 Chapter 1 Introduction Therefore, at very short contact times, enhanced mixing efficiency (i.e. high shear stress) can be achieved, which has significant effects for reactions limited by mass transfer. A high degree of conversion on the SDP has to be achieved in very short reaction times (less than 0.5 second) for observing any effective conversion.13

The SDP is a powerful tool and has been successfully used for performing polymerization reactions such as those which use free radical14,15 and condensation,16 precipitation of particles with controlled size and shape17,18 and the production of many different types of nanoparticles.19-23 Jachuck and co-workers also investigated the rearrangement of α-pinene oxide using a silica supported zinc-triflate catalyst immobilized on the surface of a SDP.24 This study highlighted the many advantages of SDP compared to a batch reactor, mainly faster reaction times due to high shear rates between the reaction medium and the catalyst (~1 sec versus 3600 secs), faster process feed (60 g/h versus 1 g/h), higher percent conversion (50% versus 85% on SDP) and no catalyst separation being required. It also has been established that SDP is an effective device in synthetic organic chemistry.

An outstanding application of SDP in synthesis is the formation of 1,5-diketones as entries to 2,4,6-triarylpyridines.25 This reaction was very successful using this device as overcomes a series of competing reactions, effectively controlling chemical reactivity and selectivity. These types of compounds are not easily accessible using normal batch stirring methods.26

B. Rotating tube processor (RTP)

The rotating tube processor (RTP) (Figure 1.3) is a new technology developed by Professor Roshan Jachuck (Clarkson University) that is based on the concepts of the SDP.27 Launched with the same thin film benefits in mind, the horizontally aligned rotating tube processor uses centrifugal forces to spread thin films of reactants with very efficient mixing. The major difference between the SDP and the RTP is the retention time of reactants on the surface. While the centrifugal forces on the disc move the reactants off of the disk quickly, the rotation of the tube swirls the reactants inside the tube around the longest axis of the tube. The RTP has jet feeds delivering solutions at one end where there is intense mixing, with the product collected at the other end. Overall, the RTP offers the ability to control the resident time, which is far greater than

Chapter 1 Introduction for SDP. Here the residence times can be minutes, depending on flow rates and the length of the tube.

Figure 1.3 Illustration of the Rotating tube processor (RTP). Taken from the Raston research group.

This technology has been successfully applied in biodiesel production,28 fabrication and formulation of drugs 29-31 and decorating of nanorods with quantum dots.32,33 However, some limitations are observed for both SDP and RTP. They both require volumes of liquid that maintain constant shear intensity in the fluids flowing over the rotating surfaces and they also have a high cost of construction which can limit the scope of their applications.

C. Vortex fluidic device (VFD)

The vortex fluidic device (VFD) is a versatile microfluidic device developed by Professor Colin Raston (University of Western Australia) in 2010.34 It involves a rapidly rotating 10 mm diameter glass tube, open at one end, encased in a thermal jacket to allow the heating and cooling of the reactant solutions. Four feed jets are used in this device, with two jets positioned to the bottom of the tube to deliver the reactant, one adjustable jet that allows for surfactant or stabilizer and another jet for gases (Figure 1.4).

Chapter 1 Introduction

Figure 1.4 Schematic of the Vortex fluidic device (VFD). Taken from the Raston research group.

This low cost compact processor has a variable angle, rotating surface and can be operated in continuous flow mode and confined mode. In the ‘confined mode’ of operation, intense shear is generated in the resulting thin film at high rotational speed for finite sub-millilitre volumes of liquid, depending on the speed and orientation of the tube, and other operating parameters. Residence time can vary in this mode depending on the nature of the reaction. It can also operate under ‘continuous flow mode’ with jet feeds delivering liquid into the rotating tube where additional shear is generated in the thin films from the viscous drag as the liquid whirls along the tube. Residence time of this mode can also be controlled by changing the variable parameters and both modes have high heat and mass transfer.35

The main advantage of this technology includes the small volume of liquid (1-2 mL) that can be used whereas in comparison to SDP or RTP which require >100 mL of liquid. Another advantage includes the ability to vary the residence time in confined mode. Variation of tilt angle is also a very important feature of this device due to the ability to incrementally adjust the shearing and mixing forces of reactants. In this way, the VFD allows the different types of reactions to be undertaken based on the interplay of these effects.

Chapter 1 Introduction

Figure 1.5 Vortex fluidic device (VFD). Taken from the Raston research group.

The Raston research group have recently established that the VFD is effective in (i) exfoliating graphite into graphene and hexagonal boron nitride (h-BN) into single sheets of the material,35,36 (ii) disassembling molecular capsules of p-phosphonic acid calix[5]arene held together by a seam of hydrogen bonds,37 (iii) controlling the decoration of palladium nanoparticles on carbon nanoonions and palladium nanoparticles on graphene38,39 and (iv) synthesis of superparamagnetic magnetite nanoparticles embedded in polyvinylpyrrolidone followed by entrapping microalgal cells within this material, and similarly entrapping them in graphene oxide.40,41 The detailed mechanism and optimization of VFD will be discussed in the Chapter 3.1.

1.2.2. Microfluidic devices as green technology

Green chemistry is a chemical philosophy encouraging the design of products and processes that reduce or eliminate the use and generation of hazardous substances. The chemical sector has long been observed by wider society as being ‘dirty’. Nevertheless, considerable amounts of research have been performed into the development of ‘green’ techniques for chemical synthesis in the last few decades, through the goal being to decrease the waste generation from the chemical industry.42

Paul Anastas developed twelve principles of green chemistry,43 which help to explain what the definition means in practice. The principles cover such concepts as:

Chapter 1 Introduction • The design of processes to maximize the amount of raw material that ends up in the product. • The use of safe, environment-benign substances, including solvents, whenever possible. • The design of energy efficient processes. • The best form of waste disposal.

These above concepts are totally compatible with process intensification approaches which incorporate so many operations into a single entity. As a result it has been applied to processes in the chemical, pharmaceutical and bio-based industries.44 Microfluidic devices are clearly miniaturized and can easily be implemented into process intensification.1,45 This results in smaller plants, hence with lower costs in capital and energy, reduced environmental impact, operating in a contained, well controlled and safer environment.45 Microfluidic devices may significantly decrease the processing time to market, which is a vital issue in some sectors such as the fine chemical and pharmaceutical industries. In fact, microfluidic devices allow for the quick application of a continuous process developed on a lab-scale as the commercial scale process.1

1.3 Triaryl and polysubstituted pyridines

1.3.1 Application and structure

Pyridine derivatives have occupied a unique position in medicinal chemistry because of the occurrence of their saturated and partially saturated derivatives in biologically active compounds and natural products such as NAD nucleotides, pyridoxol (vitamin B6), and pyridine alkaloids46. Literature reports have already established pyridines as anti-malarials, vasodilators, anesthetics, anti-convulsants, anti-epileptics and agrochemicals such as fungicides, pesticides, and herbicides.47-50 Trisubstituted pyridines are prominent starting materials in both organic and inorganic supramolecular chemistry, with their π-stacking ability and coordination properties along with directional H-bonding capacity.51-55 In addition, the excellent thermal stabilities of these pyridines have instigated a growing interest for their use as monomeric building blocks in thin films and organometallic polymers.56-59

Chapter 1 Introduction

(i) (ii) (iii) (iv)

4' 3' 5' 3' 4' 5' 3 4 5 3 5 4 2 6 N N N N 6 6" 6 N 6" N N 2 N 6 5 3 3" 5" 5 3 3" 5" 4 4" 4 4"

Figure 1.6 Representative structures of (i) 2,2´:6´,2´´-terpyridine, (ii) 4´-aryl- 2,2´:6´,2´´-terpyridine (iii) 2,4,6-triarylpyridine and (iv) polysubstituted pyridine.

Terpyridine (Figure 1.6, i and ii) has been extensively studied as a complex agent for a wide range of transition metal ions with this application being the result of a great advance in the design of terpyridine and its derivatives in the last decade. The well- known characteristics of terpyridine metal complexes, such as their special redox and photophysical properties, depend on the electronic influence of the substituent. Therefore, terpyridine complexes have the ability to be used in photochemistry for the design of luminescent devices60 or as sensitizers for light-to-electricity conversion.61,62 Ditopic terpyridyl units also form polymetallic species which can be used to prepare luminescent or electrochemical sensors.63,64 In clinical applications, functionalized terpyridines have found a wide range of potential uses65 ranging from colorimetric metal determination66,67 to DNA binding agents68-70 and antitumor research.71-73

2,4,6-Triarylpyridines known as Krohnke pyridines (Figure 1.6, iii) are structurally related to symmetrical triaryl-thiopyrylium, triarylselenopyrylium, and triaryl- telluropyrylium photosensitizers, which have been recommended for photodynamic cell specific cancer therapy.74 Recent studies have highlighted the biological activity of 2,4,6-triarylpyridines, providing impetus for further studies in utilizing this scaffold in new therapeutic drug classes.75-77 These molecules have been found to be useful for the synthesis of DNA binding ligands, in particular targeting G-quadruplex DNA that has recently received much attention as a possible target in cancer therapy.78-81

The general structure of 2,4,6-triarylpyridines (TAPs, Figure 1.6, iii) and polysubstituted pyridines (Figure 1.6, iv) offer an attractive template for ligand design. TAPs have three rotatable bonds making it an important structural feature that provides potential for different conformations while retaining a degree of rigidity. TAPs also have similarity to α-helix mimics that have been based on linked aryl groups.82 The TAP scaffold also allows for identification of the quadruplex, whereby each quadruplex

Chapter 1 Introduction is distinguished by the central core orienting side chains to target the hypervariable loops, thereby providing the prospect for G-quadruplex discrimination.83

1.3.2 Central ring assembly synthesis of trisubstituted pyridines

The central ring assembly and coupling methodologies are the two basic synthetic approaches to trisubstituted pyridines. Ring assembly although the most common strategy (which will be further discussed in this introduction) has been surpassed in some areas by modern palladium-catalyzed cross-coupling procedures because of their multiplicity and efficiency. Appropriate methodologies for the construction of variously functionalized trisubstituted pyridine ligands have been derived from directed cross- coupling procedures.84

1.3.2.1 Krohnke condensation reaction

The Krohnke condensation reaction is the most well-known method for the synthesis of trisubstituted pyridines which initially involves the synthesis of a pyridinium salt (e.g 1, Scheme 1.1). Then the formation of the in situ 1,5-diketone, 3 is achieved through a Michael addition involving the salt, 1 and an unsaturated ketone, 2 with ammonium acetate in glacial acetic acid (methanol and water can be used). The diketone, 3 which is only rarely isolated, undergoes ring closure on treatment with ammonium acetate to give the symmetrical or unsymmetrical trisubstituted pyridine, 4 (Scheme 1.1).85 The main advantage of this reaction is that the substitution pattern of the two components can be varied as desired.

However, a problem with the Krohnke condensation is that, the product requires purification which is time consuming and complex and in some cases can lead to very low yields of product. Moreover, the starting material of this reaction is not readily available and must first be synthesized. In scheme 1.1, R1, R2 and R3 were referred as aromatic and aliphatic group.

Chapter 1 Introduction

O 3 R 3 2 3 R R OR O 2 + + N N - 2 1 NH OAc, AcOH/MeOH Br R 1 2 R - 4 R N R Br 1 R O 1 3 4

Scheme 1.1 Krohnke condensation synthesis of trisubstituted pyridines.

1.3.2.2 Improved Chichibabin reaction

Another familiar and widely used method for the synthesis of trisubstituted pyridines is the modified Chichibabin reaction. This reaction involves refluxing a 2:1 mixture of an aromatic aldehyde (6) and aryl methylketone (5) in the presence of glacial acetic acid and excess ammonium acetate (Scheme 1.2). The mechanism of this reaction involves

2 O R O 2 O O R H 1 6 R 2 1 1 R R R 1 NH4OAc, AcOH R O 5 7 8

2 R 2 R O H

2 1 1 1+ R R 1 1 NR R R N R H 10 9

Scheme 1.2 Modified Chichibabin reaction for synthesis of triarylpyridines. an initial acid-catalysed aldol condensation of the enol form of the aryl methylketone with the aryl aldehyde, in a 1:1 molar ratio to form the enone, 7, which subsequently undergoes a Michael addition reaction with another equivalent of aryl methylketone to produce a 1,5-diketone, 8. This 1,5-diketone, 8 then condenses with ammonia to form a dihydropyridine (9). Finally, 9 is dehydrogenated to a trisubstituted pyridine, 10 along with a saturated enone.86 Yields of 60-68% were reported by Weiss for a series of triarylpyridines.86

Chapter 1 Introduction 1.3.2.3 Potts method

Potts et al. has reported a one pot two-component procedure involving the in situ generation of unsaturated α-diketones, 13 derived by reaction of a α-ketoketene dithioacetal, 11 and methylketone carbanion, 12 (Scheme 1.3). Reaction of these enediones, 13 with ammonium acetate in hot acetic acid provides the 2,6-disubstituted- 4-(methylthio)pyridines, 14 in 60-99% yield.86 The main limitation of this method is that the final condensation step usually produces tar-like crude products, which require extra effort to isolate and purify the desired trisubstituted pyridine compounds. In the scheme 1.3, R and R1 were referred as aromatic and aliphatic group.

O O O S 1 - + R CH2K O R NaH/Me2SO 12 R O NH4OAc, AcOH R - 1 1 CS2, CH3I S S + SC R K R N R H 11 13 14

Scheme 1.3 Potts method for the synthesis of trisubstituted pyridines.

The synthesis of trisubstituted pyridines from the above methods all have major disadvantages and limitations. The Krohnke85 and Potts et al.86 methodologies suffer from low yields, utilising large volumes of volatile organic solvents, have low atom efficiency and often involve multiple purification steps. Furthermore toxic and expensive organic solvents such as halogenated solvents pyridine are used in these methods that produce large volumes of halogenated waste. Dehydrogenation of dihydropyridine in the Chichibabin method also limits the yield on the reaction.87

1.3.2.4 Solvent-free grinding reactions

The major challenge for the drive towards benign chemical technologies is eliminating organic solvents from chemical synthesis. Selectivity, stereochemistry, yield, waste, viscosity, ease of recycling, energy usage, ease of isolation of products, competing reactions and heat of reaction are the vital issues for the choosing of a solventless or specific/non-organic solvent reaction medium. An innovative and indeed more versatile protocol has been established by Raston et al, based around the principles of Green Chemistry.88-90 13

Chapter 1 Introduction Using a solvent-free method the aldol condensation of an enolisable ketone, 15 and a benzaldehyde, 16 followed by Michael addition of the enone, 17 (Scheme 1.4), with a second enolisable ketone was achieved. Both steps were treated under solvent-free conditions involving grinding with solid sodium hydroxide to give a 1,5-diketone, 18. The diketone 18 can be either symmetrical or unsymmetrical in structure depending on the ratio of reactants and order of addition.88-90 In the presence of ammonium acetate in acetic acid, a Krohnke-type pyridine, either a terpyridyl or a bipyridyl or pyridine, 19, is then rapidly formed in high yield through a double condensation (Scheme 1.4). In scheme 1.4, R2 was indicated as hydrogen and R1, R3 were referred as aromatic group.

2 O 2 2 2 R R R O R 3 NaOH(S) R O NH4OAc, AcOH 1 R + Grind NaOH 3 [O] (S) R O Grind 1 1 1 3 R O R O NR R 15 16 17 18 19

Scheme 1.4 Solvent-free grinding procedure for the synthesis of unsymmetrical triarylpyridine.

A series of 4´-(4-alkoxyphenyl)-4,2´:6´,4´´-terpyridines was accessed using the solvent-free grinding method which could not be synthesized using solvent-based methods.88 In the solvent-based methodology the major product is a cyclohexanol derivative (Figure 1.7), which results from the condensation of the enone and 1,5-diketone.88-90 Anderson et al. described the synthesis of 4´-(4-alkoxyphenyl)- 4,2´:6´,4´´-terpyridines with only a moderate 6% overall yield under somewhat harsh conditions,91 compared with 84% yield using the solvent-free grinding approach.88-90

O N

N OH R O

Figure 1.7 Cyclohexyl product. Adapted from the Reference 89.

Chapter 1 Introduction However, the solvent-free methodology is limited and even though the method gave access to 4´-(aryl)-terpyridines in high yield, it was unsuccessful in gaining access to 4´- (pyridyl)-terpyridines. The 1,5-diketone intermediate that is needed to synthesize 4´- (pyridyl)-terpyridines was not accessible under solvent-free conditions and as the reaction is exothermic in nature it resulted in a black, tarry intractable residue.92

1.3.2.5 Using PEG as a reaction medium

With the intention of minimizing these above problems and keeping up the theme of green chemistry, Raston et al. reported the use of poly(ethylene glycol) (PEG) as a versatile reaction medium in gaining access to 4´-(pyridyl)-terpyridines.92 PEG is becoming important as a benign, alternative reaction medium in synthetic chemistry. Generally PEG is a non-toxic chemical, as it is used in food products and cosmetics. In addition it is potentially recyclable and water-miscible which assists its elimination from reaction products.93

In a typical experiment, a 2:1 molar ratio of 2-acetylpyridine and 4- pyridinecarboxaldehyde (Scheme 1.5) were used to form the 1,5-diketone, 21. 2- acetylpyridine was added to a cooled (0°C) suspension of crushed sodium hydroxide in PEG and this resulted in the formation of a yellow mixture containing presumably the enolate anion, 20. After 10 minutes the aldehyde was added to the reaction mixture. The reaction mixture was allowed to stand for 2 hours with intermittent manual stirring (ca. every 15 minutes). After this time a sticky emulsion formed but after adding water, the material solidified on standing overnight at 5°C. After isolation of this material and washing with water and cold ethanol it resulted in the 1,5-diketone, 21 as a white solid.92

Of added interest was that direct access to terpyridine, 22 in one-pot through the addition of excess ammonium acetate after the 2 hours during the initial reaction was possible which can avoid the isolation of 1,5-diketone intermediate, 21 (Scheme 1.5). After 2 hours at 100 °C, the mixture was cooled and water added to remove PEG, which gave a microcrystalline precipitate of pure 4´-(pyridyl)-terpyridine, 22. In this method, any side products or unreacted intermediate products (chalcone or 1,5-diketone) were not present, which is in contrast with the traditional method. The reaction yield (ca. 54%) is acceptable in the context of the short reaction times (4 hours compared to 24

Chapter 1 Introduction hours for the traditional method) and the high purity of the end product. This method also avoids the use of costly, volatile organic solvents associated with labour intensive purification methods. There was no significant increase in the reaction yield even with prolonging the reaction time.92

N N O N N N O H NaOH NH4OAc PEG N - O O 2CH O N N N 20 N 21 22

Scheme 1.5 PEG method for the synthesis of symmetrical 4′-(pyridyl)-terpyridine.

Unfortunately, this method is not very effective at room temperature, with the major product being the cyclohexanol compound (Figure 1.7) derived from further aldol condensation of 1,5-diketone and enone.92

Winter et al.94 has also implemented the PEG method for the synthesis of 4´-(aryl)- terpyridines. However, in this case aqueous ammonia is used instead of ammonium acetate for the ring closure step. Thus, the amount of inorganic salts was reduced significantly making the reaction sequence even more friendlier to the environment. Yields of 22-63% were obtained for a selection of 4´-(aryl)-2,2′:6′,2′′-terpyridines.94

The synthesis of 4´-aryl-2,6-bis(4-aminophenyl)pyridines (25), from 4´-aryl-2,6- bis(4-nitrophenyl)pyridine (24) (Scheme 1.6) were recently reported by Tamami and Yeganeh.95 They used a modified acid-catalysed Chichibabin method for synthesizing 24 which was followed by isolation and purification. Then, the nitro groups on 24 were

Ph Ph

O O NH OAc, AcOH N H .H O + 4 N 2 4 2 N Ph Pd/C, EtOH O N NH NH 2 O2N NO2 2 2 23 24 25

Scheme 1.6 Procedure for the synthesis of 4´-aryl-2,6-bis(4-aminophenyl)pyridines. reduced with hydrazine hydrate to access 25. Despite the ease of preparation this method uses excessive amounts of volatile organic solvents and hydrazine hydrate, which is a corrosive potential carcinogen.

Chapter 1 Introduction In order to resolve this problem, Raston et al. developed a straightforward one pot synthesis of 4´-aryl-2,6-bis(4-aminophenyl)pyridines in PEG.26 This greener methodology eliminated the need for reduction of nitro groups and reduced the use of volatile organic solvents. This method is suitable for implementation in downstream applications, such as drug development because of the involvement of mild reaction conditions and lower cost. In a general procedure, p-aminoacetophenone (26, 1 eqv.) was added to a suspension of crushed sodium hydroxide (1 eqv.) in PEG300 at ambient temperature, which presumably forms the enolate anion. The suspension was then heated to 80°C to assist in the dissolution of the reactants. This reaction mixture treated with arylaldehyde (27, 0.5 eqv) and then heated at 110 °C for 3 h. If need be, the 1,5-diketone, 28, can be isolated from the reaction mixture for further chemical elaboration or, to obtain the amino-substituted pyridines, 29 (Scheme 1.7), ammonium acetate was added after the heating period and the reaction mixture was heated further for 3h at 100°C to give 29 in good yields (76-94% yield).26

O O

+ Ar

2NH 26 27

NaOH, PEG NaOH, PEG NH4OAc

O Ar O

NH NH NH NH 2 2 2 29 2 28

Scheme 1.7 PEG method for the synthesis of symmetrical 4´-aryl-2,6-bis(4- aminophenyl)pyridines.

Nevertheless, dimethylamino-functionalized 1,5-diketones and triarylpyridine compounds could not be obtained using this method, instead the major product generated from this reactions was the Schiff base adduct or Claisen-Schimdt condensation product. The reaction was also unsuccessful in a batch process even at high temperature (140⁰C), longer reaction times (48 h) and in a microwave reactor.26 A common route often used to overcome this problem is a series of functional group protection and deprotection synthetic steps, which is inefficient and time consuming.

Chapter 1 Introduction 1.3.2.6 Using microfluidic device

The SDP is a remarkable microfluidic device in chemical synthesis (discussed in Chapter 1.2.1). This device produces thin, highly sheared films (25–200 mm) which have been shown to provide rapid heat and mass transfer as well as efficient mixing characteristics under continuous flow conditions.25 In contrast to limited heat conduction and convection in a batch reactor, the SDP contributes many influential chemical processing characteristics in a very short residence times.96

The dimethylamino-functionalized 1,5-diketone, 32, the intermediate product towards the triarylpyridine compound, 34 was synthesized using the SDP25 as it was not able to be made in normal batch processing.26 A series of multiple pass experiments were performed on a spinning disc (10 cm diameter) at various parameters (feed rates, disc speeds and temperatures) with the 1,5-diketone, 32 forming on the disc following optimization of the parameters to maximize conversion (>45%). From the study it was found that reducing the disc speed decreases the formation of the 1,5-diketone, 32, thus selectively forming the chalcone, 33 (Scheme 1.8). The 1,5-diketone, 32 is cyclised in the presence of ammonium acetate to give the dimethyl amino functionalized 4´-aryl- 2,6-bis(4-aminophenyl)pyridines (34) (94% yield) using normal batch processing .25

N N

O O O O H + SDP + N 2NH NaOH O NH NH 30 31 2 32 2 33 2NH

NH4OAc

2NH NH2 34

Scheme 1.8 Synthesis of the dimethyl amino functionalized 4´-aryl-2,6-bis(4- aminophenyl)pyridines using a microfluidic platform.

Chapter 1 Introduction Still, this method has a few limitations including the very short residence time, which means it needs several passes to complete the reaction and also the large volume of solvents needed.

1.3.2.7 Using microwave reactor and catalysts

Microwave-assisted organic synthesis has attracted considerable interest in the past decade. Microwave irradiation (MWI) is suitable for organic synthesis, which often results in decreased reaction times, increased yields, easier workups and enhanced regio- and stereoselectivity of reactions. Green chemistry principles are also consistent with the protocols of this method.

Su et al. reported the application of microwave irradiation to organic synthesis. For developing a simple and efficient synthesis towards terpyridines from available starting material, they investigated the one-pot reaction of 2-acetylpyridine, aromatic aldehydes and ammonium acetate in glycol under MWI without catalyst.97 The substituent groups of aromatic aldehydes, can tolerate the reaction conditions which resulted in excellent yields ranging from 80-91%. This method is also suitable for aromatic ketones and 1- indanones, leading to the synthesis of 2,4,6-triarylpyridines.97 However, this method used organic solvents and so was not strictly a green synthesis.

Su et al. also developed a facile and clean Krohnke reaction for the synthesis of terpyridines, triarylpyridines and polysubstituted pyridines, 37 in aqueous media using either MWI or conventional heating conditions (Scheme 1.9). The results indicated that MWI exhibited several advantages over conventional heating (80%) by significantly reducing the reaction time and improving the reaction yields (90-97%).98 The scope of the reaction regarding the aldehydes was studied and found that the substituted groups (R) of aromatic aldehydes, such as electron-withdrawing groups and electron-donating groups, can tolerate the reaction conditions with excellent yields.

Yin et al. reported the synthesis of hydroxylated trisubstituted pyridines under MWI (30 min, 70-86% yields) and they also investigated the photophysical properties of these pyridines.99 Recently several improved methods using catalysts have been developed for the synthesis of triarylpyridines which include ionic liquids,100,101

Chapter 1 Introduction heteropolyacid,102 bismuth triflate,103 L-proline,104 Cu coupling,105 catalytic amount of 106 107 108 acetic acid, HClO4–SiO2 and PPA-SiO2.

NH4OAc R + H O 2 N

CHO 35 36 37

Scheme 1.9 Microwave irradiation (MWI) synthesis of polysubstituted pyridine.

1.4. Calix[4]arenes

A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde.109 The word calixarene is derived from calix or chalice because this type of molecule resembles a vase and from the word arene that refers to the aromatic building block. Calixarenes have hydrophobic cavities that can hold smaller molecules or ions and belong to the class of cavitands known in host-guest chemistry.

1.4.1 History of Calix[4]arenes

Calix[4]arenes have a long history, stretching back to 1872 when Adolf von Baeyer reported reactions of phenol with aldehydes obtaining a crystalline product.110 Several years later, Michael111 established the correct elemental composition of this sparingly soluble, high melting, crystalline product (C13H10O2)n and its acetyl derivative

(C13H8(OCOCH3)2)n. From these data, he also concluded that the product is formed by combination of an equal number of benzaldehyde and resorcinol molecules and loss of an equal number of water molecules. Michael suggested a structure for the product which was later accepted112 and has been cited in polymer chemistry.113

Chapter 1 Introduction

OH OH

R R OH OH

OH OH R R OH OH R= Alk or Ar

Figure 1.8 Structure of calix[4]resorcinarene molecule.

Later, Niederl and Vogel114 studied several condensation products obtained from the reaction between aliphatic aldehydes and resorcinol. They concluded that the ratio between aldehyde and resorcinol in the product should be 1:1 by molecular weight determinations. They proposed the cyclic tetrameric structure (Figure 1.8) (R = aliphatic or aromatic) analogous to cyclic tetrameric structures frequently encountered in nature, e.g porphyrins. This structure was finally confirmed in 1968 by Erdtman and co- workers using X-ray crystallographic analysis.115 These compounds are known by a host of trivial names which include calix[4]arenes,116 Högberg compounds,117 octols118,119 and recently resorcinarenes (resorcinol as starting material) became the staple term used in the literature.120

1.4.2 Application of calix[4]arenes

In recent years calix[4]arene chemistry has moved in many directions. It has been used in a wide range of applications since their first synthesis as supramolecular tectons,121 NMR chiral shift agents,122 liquid crystals,123,124 fluorophores,125,126 HPLC stationary phases,127,128 catalysts,129,130 metal ion extractors,131,132 surface reforming agents133 and molecular receptors.126,134

Atwood and co-workers135 have demonstrated the formation of C-n- hexylpyrogallol[4]arene-based organic nanotubes in the solid state that show some potential to maintain their structure in solution. C-Undecylcalix[4]resorcinarene-capped anatase (TiO2) nanoparticles have been synthesized; they could be isolated and then redispersed in different nonaqueous solvents.136 Self-assembled solid lipid nanoparticles based on prolyl-appended resorcinarene have also been chemically modified with 21

Chapter 1 Introduction bovine serum albumin and have been studied with regard to interactions with surface bound anti-albumin antibodies.137

1.4.3 Stereochemistry of calix[4]arenes

Calix[4]arenes are non-planar molecules and exist in different isomeric forms.119,138,139 The stereochemistry is generally defined by a combination of the following three stereochemical criteria (these criteria are not independent): (i) The conformation of the macrocyclic ring which can adopt one of five highly symmetrical conformations, viz, crown (C4v), boat (C2v), chair (C2h), diamond (Cs) and saddle (D2d) (Figure 1.9).

Figure 1.9 Conformations of calix[4]arene. Taken from the Reference 141.

(ii) The relative configuration of the substituents at the methylene bridges, which can be all-cis (rccc), cis-cis-trans (rcct), cis-trans-trans (rctt) or trans-cis-trans (rtct) arrangement (Figure 1.10).140

Chapter 1 Introduction

Figure 1.10 Relative configurations of calix[4]arene. Adapted from the Reference 140.

(iii) The individual configuration of methylene bridge substituents, which may be either axial or equatorial in macrocycles with C-symmetry.141

The combination of these three criteria results in an immense number of possible stereoisomers. Nevertheless, only several of them have ever been reported experimentally. For example, the two boat isomers interconvert quickly and give a time- averaged crown conformation, thereby the `boat' conformation is usually referred as a `crown' conformation. However, the interconversion between boat, chair and diamond isomers does not occur, since it would require the breaking of a minimum of two covalent bonds. These isomers are reported as diastereomeric isomers, and all of them can be formed in a reaction. In general, the thermodynamic stability of the different isomers under homogeneous acidic conditions determine the product ratio, as the condensation reaction is reversible under such conditions.142 When the reaction is performed under heterogeneous conditions, the relative solubility of the different isomers plays a vital role in determining the product ratio.139 The ratios of diastereoisomers formed in a reaction also depends on the reaction conditions used, while there are many factors that may influence the presence or absence of a specific isomer.140 Furthermore, the conformational properties of free hydroxyl containing calix[4]arenes are influenced by the solvent and the formation of intra- and intermolecular hydrogen bonds.

1.4.4 The mechanism of calix[4]arene condensation

The mechanism of the acid-catalyzed condensation reaction of calix[4]arenes has been studied extensively142 (Scheme 1.10). In the condensation reaction of resorcinol

Chapter 1 Introduction

OH OH OH OH + OH OH OH OH OH OH O + O H + H H -H2O + HR OH O H + HR 2 C H R R R

OH OH OH OH OH OH OH OH OH OH OH OH OH OH

RCHO RCHO R R R

OH OH

R R OH OH

RCHO

fast OH OH R R OH OH OH OH OH OH OH OH OH OH

R R R Higher oligomers R= Alk or Ar.

Scheme 1.10 The reaction of cyclocondensation of calix[4]arene.Adapted from the Reference 141. and an aldehyde, the protonated aldehyde is the initial electrophile, which adds to the resorcinol by electrophilic addition. The alcoholic hydroxyl of the following adduct is protonated again to remove water. A carbocation intermediate is formed by the loss of the water molecule, which undergoes a second electrophilic addition to another resorcinol to form a dimer. Sequential couplings of the dimer with other resorcinol units produces trimers, tetramers, or higher oligomers containing more than four monomers. As the condensation reaction is reversible under acidic conditions, most of the higher oligomers are consumed toward the end of the reaction, although they are present during the intermediate stages of the reaction. The linear tetramers cyclize quickly to form calix[4]arenes after forming in the reaction mixture.141

1.4.5 Synthesis of calix[4]arenes

1.4.5.1 Resorcinol-Aldehyde condensations

The acid-catalyzed condensation of resorcinol or substituted resorcinol with various aliphatic or aromatic aldehydes results in calix[4]arenes. The condensation occurs on heating the reactants to reflux in a mixture of ethanol and concentrated HCl for several hours. Usually, the cyclotetramer crystallizes out from the reaction mixture in

Chapter 1 Introduction reasonable to high yields in a simple one-step reaction; although for different aldehydes different optimal reaction conditions exist.117,119,143 It is very difficult to get tetrameric products when the resorcinol used contains an electron-withdrawing substituent, such as nitro- or bromo- group moiety at the 2-position.119 Under certain conditions, reactions of formaldehyde, 2-methylresorcinol or pyrrogallol yield isolatable amounts of the tetrameric product.144 Cram and co-workers119 and Weinelt and Schneider142 studied at which point on the resorcinol ring condensation occurs and found varied results.

1.4.5.2 Other types of condensation reactions

A series of C-alkoxycarbonylmethylcalix[4]resorcinarenes (39) have been synthesized through a versatile route using 2,4-dimethoxycinnamates (38) as starting materials under carefully controlled reaction conditions. In this method boron trifluoride was used as a Lewis acid catalyst (Scheme 1.11).145,146 The stereoselectivity of the cyclization appears to be dependent on the reaction conditions and the nature of the side chains at the bridging carbon atoms. The compound, 39 represents two conformers, viz., a flattened cone (cis-cis-cis or rccc) and a 1,2-alternate (cis-trans-cis or rctc) which were established by 1H and 13C NMR spectroscopic studies.145,146 In the case of calix[4]resorcinarenes, 39 synthesis, the third conformer, 1,3-alternate (rtct) appears with pseudoequatorial side chains.

MeO OMe

CH2CO2R RO2CH2C MeO OMe MeO OMe

BF3.Et2O

 CHCl3, 20 C, 15 h MeO OMe OR CH CO R RO2CH2C 2 2 O MeO OMe 38 39

Scheme 1.11 Synthesis of calix[4]arene, 39 using Boron trifluoride.

The Lewis acids, thionyl chloride, phosphoryl chloride, aluminium chloride, dimethyldichlorosilane and tin(IV) chloride catalyze the cyclocondensation of 1,3- dimethoxybenzene with isovaleraldehyde to produce high yields of the corresponding resorcinarene 40 (Scheme 1.12).147 Selective formation of the crown conformer (rccc)

Chapter 1 Introduction in high yield (85%) was obtained from using the only catalyst SnCl4, amongst all the Lewis acids tried.

MeO OMe i i Bu Bu MeO OMe MeO OMe i Bu CHO, CHCl3

L.acid, Et2O, 24h MeO OMe i i Bu Bu MeO OMe 40

Scheme 1.12 Synthesis of calix[4]arene, 40 under Lewis acid catalyst.

A novel synthetic methodology for fully selective formations of the rctt chair stereoisomers of octa-O-alkyl resorcin[4]-arenes, 41 in acetic acid-salfuric acid or acetic acid-hydrochloric acid mixtures has been reported (Scheme 1.13). It has been proposed148 that this isomer is the thermodynamic product under BrØnsted acid catalysis, which is a unique observation in resorcinarene chemistry. Here, R= substituted aromatic or aliphatic groups.

MeO OMe

R R MeO OMe MeO OMe RCHO B acid MeO OMe R R MeO OMe 41

Scheme 1.13 Synthesis of calix[4]arene, 41 under BrØnsted acid catalyst.

The condensation of 2,6-dihydroxypyridine with a number of aliphatic (R) and two aromatic (R) aldehydes in acidic media formed a new type of octahydroxypyridine[4]arene, 42 (Scheme 1.14).149 The reactivity of 2,6- dihydroxypyridine is less than that of resorcinol or pyrogallol, so harsher conditions are involved in this method. But in principle, the cyclization reactions are comparable with other methods.

Chapter 1 Introduction

OH N OH

R R OH OH

OH NOH RCHO N N H+ OH OH R R OH N OH 42

Scheme 1.14 Synthesis of octahydroxypyridine[4]arene, 42.

Another example of calix[4]arene synthesis involves the cyclocondensation of 1,3- dialkoxybenzenes with 1,3,5-trioxane catalyzed by scandium(III) triflate to produce resorcin[4]arene octaalkyl ethers, 43 as the main products (Scheme 1.15). The confused resorcin[4]arene octaalkyl ether, 44 bearing one alkoxy group at the intraannular position was also formed.150

OR OR OR OR

O OR OR OR OR OR OR O O + OR Sc(OTf)3.MeCN OR OR OR

OR OR OR OR 43 44

Scheme 1.15 Synthesis of calix[4]arene, 43 using scandium(III) triflate.

Ytterbium(III) and bismuth(III) triflates151,152 have also been reported as competent catalysts for the synthesis of calix[4]resorcinarenes. Recently, lanthanide(III) tosylates (0.1 mol%) and lanthanide(III) nitrobenzenesulfonates153,154 have also been used as efficient, inexpensive, recyclable and environmentally friendly catalysts for the synthesis of calix[4]resorcinarenes, 45 (Scheme 1.16). Their catalytic efficiency was found to be similar to that of the triflates.

Chapter 1 Introduction

OH OH

R R OH OH OH OH RCHO

Ln(OTs)3 OH OH R R OH OH

Scheme 1.16 Synthesis of calix[4]arene, 45 using lanthanide(III) tosylates.

The microwave-assisted synthesis155 of calix[4]resorcinarenes from resorcinol and aldehydes catalyzed by the Keggin-type 12-tungstophosphoric acid

(H3PW12O40.13H2O) or concentrated HCl gave excellent yields (>90%) with short reaction times (<3-5 min) and did not require harsh conditions. Pyrogallol[4]arenes, 46 have also been synthesized156 in excellent yields by the cyclocondensation of pyrogallol with aromatic aldehydes under conditions of microwave irradiation (Scheme 1.17).

OH OH OH OH CHO OH OH HCl + R EtOCH2CH2OH, MWI R 4 46

Scheme 1.17 Synthesis of pyrogallol[4]arene, 46 under microwave irradiation.

1.5 The Diels-Alder reaction

The Diels-Alder reaction involves with [4π + 2π] cycloadditions that can produce highly regio-, diastereo-, and enantioselective six membered and polycyclic ring systems. This reaction has been proved their great synthetic value in organic chemistry as constructing the six membered ring. In recent years the methods of preparation of natural products and physiologically active molecules are showing their importance in organic chemistry.157,158 Therefore, the development of special physical and catalytic methods has been increased in order to improve the rate and/or selectivity of Diels- Alder cycloadditions. 28

Chapter 1 Introduction The reaction mechanism of the Diels-Alder reaction is involved with the combination of a four-π component (typically a diene) and a two-π component, commonly termed the dienophile, forming a six membered cyclohexene system in a single reaction step (Scheme 1.18). Conformations of the reacting double bonds are fully retained in the

diene dienophile

Scheme 1.18 Schematic representation of the Diels-Alder reaction. product that makes the reaction stereospecific. Unsymmetrical dienophiles suggest two different possible transition states, which are called the endo and exo transition states, each leading to adducts of different stereochemistry. In the endo transition state, the substituent on the dienophile is oriented towards the diene π system, while in the exo it is oriented away from it. For example, Maleic anhydride and cyclopentadiene yield the endo product in a Diels-Alder reaction though for steric reasons the exo product is thermally the more stable one. Only by heating to 200⁰C the endo isomer is transformed into the more stable exo isomer.157

1.5.1 History

The two German scientists Otto Diels and Kurt Alder extensively studied the synthetic and theoretical characteristics of [4π + 2π] cycloadditions. The Diels-Alder reaction was named after them and their outstanding work in synthetic chemistry has been rewarded with the Nobel Prize in chemistry in 1950. However, their work is shrouded in some controversy as the first Diels-Alder-type reaction (the dimerisation of tetrachlorocyclopenta-dienone) was reported in 1892159,160 and in 1920, von Euler first recognized the importance of this reaction.161 Eight years after this report, Diels and Alder published162,163 their work. They also performed consecutive studies on the reaction that proved the versatility of the Diels-Alder reaction in synthetic organic chemistry. Recently, Berson164 published a detailed historical story of the chemistry and the chemists involved in the discovery of the Diels-Alder reaction.

Chapter 1 Introduction 1.5.2 Acceleration and selectivity enhancement of Diels-Alder reaction

Aromatic molecules are very common in nature and have intrinsic stability. For this reason they do not usually act as dienes in Diels-Alder reactions. The standard aromatic system benzene needs to overcome a 20-40 kcal/mol thermodynamic barrier to be reactive enough for a Diels-Alder reaction,165,166 therefore, a very small number of publications based on the Diels-Alder reactions with aromatic compounds have been reported.167,168 Basically there are two types of approaches used in those publications that can overcome the resonance energy of aromatic compounds. One technique is relief of strain in distorted aromatic cores which compensates for the loss in aromaticity.169,170 The other technique is the use of harsh conditions such as high temperatures and pressures or the use of strong Lewis acids that can enhance orbital interactions.171,172

1.5.2.1 High pressure acceleration

The Diels-Alder reactions have large negative activation volumes (about 25 to 45 cm3 mol-1)173 as well as large negative volumes of reaction. The use of high pressure

O O CO2Me CO2Me H 15 kbar, RT + H O O 47 48 49

Scheme 1.19 Diels-Alder reaction at high pressure.

(typical range is from about 1 to 25 kbar) can accelerate the intermolecular Diels-Alder reactions to overcome the reaction barrier. The high-pressure kinetic method171 is very effective in understanding the structure and the properties of the transition state in Diels-Alder reactions. Heat sensitive or very poor reactivity compounds also perform the Diels-Alder cycloaddition under these conditions. For example, the Diels-Alder reaction of 1,4-benzoquinone (47) with methyl 2,4-pentadienoate (48) to provide 49 proceeds in good yield (60%) at room temperature under 15 kbar pressure (reaction time 18 h) (Scheme 1.19).174 However, the product yield was significantly lower (28%) at atmospheric pressure. 30

Chapter 1 Introduction 1.5.2.2 Using Lewis acid catalysis

Lewis acid catalysts have dramatic effects on the reaction rate and the selectivity of the Diels-Alder cycloaddition. The reaction rate increases compared to their thermal counterpart as well as regio- and stereoselectivity is observed in the presence of Lewis acid. As a result of an exceptional reactivity-selectivity principle, such reactions are of additional interest from a theoretical point of view. Yates and Eaton first discovered the notable effects of Lewis acid on the rate of the Diels-Alder reactions.175 Their study involved with the reaction between maleic anhydride and anthracene in the presence of aluminium trichloride (Lewis acid). Surprisingly, this reaction needs only 1.5 miniutes to complete while they projected the required reaction time for the same reaction to be around 4800 hours in the absence of Lewis acid. Later, Sauer and Kredel revealed the effect of Lewis acids on the selectivity of the Diels-Alder reactions.176 They investigated that the endo-exo selectivity of the reaction between cyclopentadiene and methyl acrylate increased from 82% to 98% endo in the presence of AlCl3.OEt2 (Lewis acid). Furthermore, upon addition of Lewis acid, the regioselectivity177 and the diastereofacial selectivity178,179 of cycloaddition reactions was also enhanced.

Figure 1.11 HOMO-LUMO arrangements for Lewis acid catalysed (broken line) and uncatalyzed (solid line) Diels-Alder reactions with normal electron demand. Taken from the Reference 180.

Chapter 1 Introduction Reagents having Lewis-basic sites close to the reaction centre are the main advantage for the favourable effects of Lewis acids. Fortunately, in almost all Diels-Alder reactions one of the reagents, mainly the dienophile, fulfils this criterion. A lone pair on one of the reactants is involved with the coordination. Frontier Molecular Orbital (FMO) theory can successfully explain the role of the Lewis acids in Diels-Alder acceleration. Donor-acceptor interactions between the dienophile and the catalyst thus lower the energy of the HOMO and the LUMO of the dienophile and, in turn, an increase in the rate of the Diels-Alder reaction (Figure 1.11).180 For example, protonated acrolein is one of the simplest dienophile-Lewis acid complexes which can explain the mechanism of the effects of Lewis-acids on selectivity.181

1.5.2.3 The effect of water on Diels-Alder reactions

Although ubiquitous in nature, for a long time water was not a very popular solvent for Diels-Alder reactions. Only few examples of Diels-Alder reactions in water were reported before 1980. The reaction between furan and maleic acid is a common example of the Diels–Alder reaction. In 1931, Diels and Alder themselves performed this reaction in an aqueous medium.182 However, the same reaction was again done by Woodward and Baer in 1948183 using different solvents as well as in water and they observed a change in endo-exo selectivity in water. Eggelte et al. also explored the same reaction and found a positive rate of the Diels-Alder reactions in water.184 Furthermore, two patents report Diels–Alder reactions with water.185,186 After pioneering works of Breslow et al., it became more established that water was a unique medium for Diels– Alder reactions.187 Usually, the rate of the Diels–Alder reactions increases significantly using an aqueous medium, as compared to all other organic solvents. Accelerations can exceed a factor of 104 in extreme cases.188 Furthermore, aqueous solvents tend to increase the selectivity as well as regioselectivity and diastereofacial selectivity of the reaction with the generally observed preference for the formation of the endo-cyclo adduct being more pronounced in water.188

1.5.2.3.1 The effect of water on the rate of Diels-Alder reactions

The acceleration of Diels–Alder reactions in water was explained by Breslow and Rideout187 in terms of a hydrophobic effect but the acceleration is sometimes attributed 32

Chapter 1 Introduction to micellar catalysis.189 Solvent effect studies directed to useful insight into the basis of the special rate effect of water on the Diels-Alder reaction. Gajewski reported the importance of the cohesive energy density (ced) together with the hydrogen-bond donating capacity of the solvent, by a multi parameter analysis.190 The ced is very effective in measuring the solvophobicity of water in the Diels-Alder reaction.191 This also highlights the importance of hydrophobic interactions of water on the reaction. “Enforced hydrophobic interactions” is the best term to describe this special type of hydrophobic interaction192 whereas, the term “enforced” described the fact that the involvement of the nonpolar reagents is increased by water.

Other solvents effect on the Diels-Alder reaction also revealed that reactivity of the reaction is primarily determined by the hydrogen-bond donating capacity and the solvophobicity. Large number of authors established the effect of these two parameters and this pattern strongly suggests that in water, a hydrogen-bond donating solvent benefits the Diels–Alder reaction not only from enforced hydrophobic interactions but also from hydrogen-bonding interactions.188 Due to the small size of water molecules, they can easily interact with hydrogen-bond acceptors to form more hydrogen bonds than other protic organic solvents.193

1.5.2.3.2 The effect of water on the selectivity of Diels–Alder reactions

Breslow et al. revealed that the endo-exo selectivity of the Diels-Alder reaction benefits noticeably from using aqueous media194,195 with hydrophobic effects as the most important contributor to the enhanced endo-exo selectivity based on the influence of salting-in and salting-out agents. Hydrophobic effects are believed to stabilize the more compact endo-transition state more than the extended exo-transition state. The well-known smaller activation volume for the endo-cycloaddition is marked for the variation in compactness of both states.196 As well, the high polarity of water is believed to reinforce the preference for endo-cycloadduct. In fact, Berson et al. reported the sensitivity of the solvent on the endo-exo product ratio.197

The importance of hydrogen-bonding interactions besides the solvophobic interactions and polarity effects on the endo-exo selectivity of Diels–Alder reactions have also been rationalised.198 Additional evidence for the impact of the former interactions have been obtained from computer simulations199 and from the similarity

Chapter 1 Introduction with Lewis-acid catalysis which is well known for increasing the endo-exo selectivity significantly.

In brief, the effect of water has on the endo-exo selectivity appears to come from three characteristics which all favour formation of the endo-adduct: (1) strong hydrogen-bond donor, (2) polar and (3) induces hydrophobic interactions.188

1.5.2.3.3 The effect of additives on the rate and selectivity of Diels- Alder reactions in water

The effect of addition of chaotropic and anti-chaotropic salts on the rate of aqueous Diels-Alder reactions has also been demonstrated by Breslow et al.187 Chaotropic salts are salting-out agents that can decrease the solubility of nonpolar compounds in water by preventing the formation of a cavity to accompany the solute. On the other hand, anti-chaotropic salts act as salting-in agents and are involved in direct solvation of the solute.200 Upon addition of lithium chloride (a salting-out agent) results in a delay in the intramolecular Diels-Alder reaction, whereas, calcium chloride (salting-in agent) boosts the efficiency of this reaction.201

The addition of small amount of alcohol to water medium also increases the reaction rate of Diels-Alder reactions. Blokzijl widely studied the effect of different alcohols in this cycloaddition192,202 and found that alcohol-water reaction solvent mixtures enhance the hydrophobic interaction and increase reaction rate. It was expected that the alcohol molecules would promote water structure, which would favour the entropy contribution of hydrophobic interactions. But the reverse was found where the alcohol molecules disturbed the hydrophobic hydration shell to enrich hydrophobic interaction.203 The addition of alcohol with water breaks down these shells and in this manner brings the entropy of activation back to normal. Therefore, small amounts of alcohol increase the activation entropy of the Diels-Alder reaction compare to pure water and the activation enthalpy is reduced upon addition of alcohol when the increased hydrophobic effects become more enthalpy-driven.203

Breslow et al. also studied the reaction between substituted maleimides and 9- hydroxymethylanthracene in alcohol-water mixtures where they showed a small amount of an alcohol co-solvent did not interfere with the ability of water to solvate ionic transition states (activated complexes), but that the co-solvent was employed to help 34

Chapter 1 Introduction solvate the hydrophobic portions. The induced solubility perturbations reflected the solvation of the reactants by the co-solvent. Overall, they successfully correlated the rate constant with the solubility of the starting materials for each Diels-Alder reaction. From these relationships they estimated the change in solvent accessible surfaces between initial state and the activated complex.204 However, this approach has limitations including the effect of hydrogen bonding interactions.

1.5.2.4 Using supramolecular catalysis

Supramolecular compounds are used as catalyst in Diels-Alder reactions. This method is becoming more popular because of the varieties in structure of compounds including cyclodextrins,205 related basket206 or capsule-like207 structures. These large molecules contain a cavity, which can effectively trap the Diels-Alder reagents and also accelerate the reaction. The same principle accounts for catalysis of Diels-Alder reactions by antibodies208 and enzymes.209 Fujita et al.210 reported that an aqueous organopalladium cage (Figure 1.12, 1) results in an unusual regioselective outcome for the Diels-Alder coupling of anthracene and maleimide guests. This cage promoted reaction at a terminal 1,4 position rather than central 9,10 position of anthracene ring. Moreover, they found another similar bowl-shaped host (Figure 1.12, 2) attaining efficient catalytic turnover in coupling the same substrates with the conventional regiochemistry (9,10 position).

Figure 1.12 Organopalladium cages. Taken from the Reference 210.

Chapter 1 Introduction 1.6 Challenges

In summary, it has been shown that PI has been established as a new paradigm in controlling chemical reactivity and selectivity. Process intensified microfluidic devices have lots of advantages over batch stirring reactions including high heat and mass transfer, controlled residence time and continuous flow processing. The VFD is unique in its design because it has two modes of operation called confined and continuous flow mode that can control the residence time. It also has variable angles and needs very small amounts of reactants and these features overcome the limitations of other microfluidic devices such as SDP and RTP. This device has already shown its capability to exfoliating graphene,35 disassembling of molecular capsules37 and the synthesis of nanoparticles.38 However, no details on the use of the VFD in synthesis of organic compounds have been reported to date.

Amino functionalized 2,4,6-triartylpyridines such as, 4’-aryl-2,6-bis(4- aminophenyl)pyridines were considered as important precursors for targeting G- quadruplex DNA but there are only limited reports for synthesizing these molecules. Smith et al. reported the PEG mediated straightforward one-pot synthesis of 4´-aryl-2,6- bis(4-aminophenyl)pyridines26 which eliminated the need for the reduction of intermediate nitro groups95 and reduced the use of volatile organic solvents. However, they were unable to synthesize dimethylamino-functionalized 1,5-diketones and the associated triarylpyridine compounds by this method, and instead the major product generated was the Schiff base adduct or Claisen-Schimdt condensation product. This reaction was also not successful in batch processing and under microwave irradiation. A novel approach was established to synthesize this dimethylamino-functionalized 1,5- diketone in a dynamic thin film, using SDP.25 Here, process intensification minimized the barriers of the relaxed fluid dynamic regime associated with conventional batch processing in chemical synthesis. Though, SDP has very short residence time, it needed several passes to get entry to the desired 1,5-diketone which is low on green chemistry metrics.

Despite the vast amount of literature available for the synthesis of calix[4]arenes, there is no reported method using continuous flow or microfluidic device technology. Traditional batch methods involve the condensation of resorcinol or pyrogallol with an aldehyde in the presence of acid and alcoholic media.119 However, the reaction time to get the thermodynamically stable crown (C4v) isomer, which is an important precursor

Chapter 1 Introduction in host-guest chemistry, is long. Also the vanillin containing resorcin[4]arenes in the

C2h symmetry chair conformation, which contains 16 O-centres has been prepared in 211 five days, with no report of C4v isomer.

The Diels-Alder reaction involving aromatic molecules are much slower relative to reactions involving aliphatic compounds due to the loss of aromatic stabilisation energy. Few strategies have been adopted to promote aromatic Diels-Alder reactions. Fujita et al.210 reported the synthesis of 9-substituted Diels-Alder cycloadducts from substituted anthracene and N-maleimide in the presence of organometallic cages. However, these organometallic cages are expensive and it also takes several hours for the reaction to occur.

These issues have been addressed in the research undertaken and described in this PhD thesis under the specific aims:

1. To optimize the Vortex fluidic device (VFD) containing a rotating surface with dynamic thin films for controlling the chemical reactivity and selectivity;

2. To employ more benign processing and give entry to the 2,4,6-triarylpyridines and polysubstituted pyridines in dynamic thin films;

3. To synthesize more preferable C4v isomer of calix[4]arenes in a very short reaction time in microfluidic platform;

4. To synthesize Diels-Alder cycloadduct of substituted anthracene and N-maleimide in dynamic thin films in aqueous media without any catalyst.

Results for each aim are reported in published articles, which establish the basis of the following chapters.

Chapter 2 Introduction to series of papers 2. Introduction to series of papers

From the literature review (Chapter 1.2.1) it is shown that the VFD is a form of process intensification involving continuous flow or confined mode with variable angles. Furthermore, it is also a versatile device and very effective in different types of applications involving dynamic thin films.

The optimization of the VFD and its application in different organic syntheses where the syntheses were not successful or very difficult to conduct in normal batch processing will be introduced in this series of papers. The optimization of the VFD will be described in the first paper (Chapter 3.1) where Diels-Alder reactions of cyclopentadiene and methyl cyclopentadiene were demonstrated as model reactions to find the optimum conditions for organic reactions. The synthesis of amino group containing 2,4,6-triarylpyridines under continuous flow via 1,5-diketone precursors and one-pot reactions will be described in the first paper (Chapter 3.1). A more benign synthesis of N,N’-dimethyl amino containing 2,4,6-triarylpyridines and polysubstituted arylpyridines using the confined mode of the VFD will be introduced in the second paper (Chapter 3.2). A facile stereospecific synthesis of calix[4]arenes under both modes of the VFD will be described in third paper (Chapter 3.3). Finally, the Diels- Alder reactions in aqueous media under dynamic thin films of VFD at confined mode will be introduced in the fourth paper (Chapter 3.4).

In Chapter 3, these papers will be presented separately.

2.1. Optimization of Vortex fluidic device (VFD)

The prototype of the VFD operates with a 10 mm diameter tube, for speeds up to 10,000 rpm and temperatures up to 200°C. The device has several reproducible operating parameters including rotating speed, tilt angle (θ) and flow rates along with operating parameters for traditional batch operated reactions, such as varying the temperature and concentration of reactants. The average film thickness for steady state conditions was established using the height of the thin film in the tube and the internal area of liquid coverage for a fixed volume of liquid. The shape of the film was found to

Chapter 2 Introduction to series of papers be quasi-parabolic and when the vortex expands to the base of the tube for high rotating speeds, it forms a uniform film. However, the fluid flow becomes more complex if the liquid does not form a complete vortex to the bottom of the tube.

The dimerization of neat cyclopentadiene (CpH) and methylcyclopentadiene (MeCpH) were investigated to realize the effect of the VFD on molecular reactions under confined and continuous flow mode respectively. These two compounds are easily dimerized at room temperature via a Diels-Alder reaction. The variable parameters of the VFD were varied out to find the optimum conditions for these dimerizations. CpH was used to study the VFD under confined mode. In this mode, as tilt angle (θ) increases the percent dimerization increases to a plateau at ca. 45⁰ then decreases before increasing again as θ reaches 90⁰ at fixed speed and time. Given the practical inconvenience of operating at this angle, especially when operating under continuous flow, the optimum shear for confined mode was set at θ = 45⁰. This angle also corresponds with the optimum angle for exfoliation of graphite and h-BN.35

At a fixed tilt angle and time, the percent dimerization increases for increasing speed. MeCpH was used to investigate the VFD under continuous flow due to the evaporative loss of cyclopentadiene at room temperature. It was found that percent dimerization of MeCpH under continuous flow increases significantly compare to confined mode. For a low constant flow rate the percent dimerization increases for increasing speed, although this is small for tilt angle, θ=0⁰. Dimerization of MeCpH under different flow rates varies dramatically for lower flow rates. At the maximum flow rate there is essentially no difference in the percent conversion with variation in θ, but significant differences develop in tracking to the lowest flow rate where the conversion increases as θ increases.

The VFD has different shear managements in the thin films. The shear depends on the tilt angle (θ) and the speed of the tube for the confined mode of operation. This was established by the increase in dimerization of cyclopentadiene relative to controls. Viscous drag dominates the shear for high flow rates at the continuous flow mode, and for low flow rates the different shear established for the confined mode also become important. This has been also established by the increase in dimerization of MeCpH relative to the controls.

The above results are compatible with the outcome of recent applications of the VFD operating under confined mode, where the optimum tilt angle was 45⁰. This includes the 39

Chapter 2 Introduction to series of papers ‘top down’ exfoliation of laminar material,35,36 the ‘bottom up’ growth of nanoparticles,38,39 disassembly of self-organised systems,37 and entrapping microalgal cells.40,41 The findings for the continuous flow synthesis are consistent with the synthesis of superparamagnetic nanoparticles for θ at 0° for a flow rate of 1 mL/min.40

Results published in:

L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston. Optimising a vortex fluidic device for controlling chemical reactivity and selectivity. Sci Rep., 2013, 3, 2282.

2.2 Microfluidic synthesis of 2,4,6-triaryl and polysubstiuted pyridines

Compounds containing pyridine rings are of considerable interest in the synthesis of pharmacological and biologically active materials. Therefore, preparation of pyridine derivatives has attracted considerable attention recently. There has been a plethora of research targeting the synthesis of both 2,4,6-triartylpyridines namely, Kröhnke pyridines, and polysubstituted pyridine compounds (details in Chapter 1.3).

4´-Aryl-2,6-bis(4-aminophenyl)pyridines were considered as important precursors for the synthesis of G-quadruplex ligands, as the amino group in these precursors allow for further functionalization to obtain the desired side chain. The optimised conditions of the VFD were used to investigate the continuous flow synthesis of 4´-aryl-2,6-bis(4- aminophenyl)pyridines (Chapter 3.1). These are formed via an aldol condensation reaction to give the chalcones, 3, followed by a Michael addition to give the 1,5-diketones, 4 (Scheme 2.1).

In some cases there is a need to get control over competing reactions, as in the unwanted Schiff base, 6a, which is a favoured product using batch processing in trying to produce the dimethylamino-functionalized 1,5-diketones via their corresponding chalcones. This unwanted product arises from poor heat and mass transfer that is overcome using the SDP. But the SDP requires multiple passes because of the short residence time (<1 second for a 10 cm disc).25 A single pass, under continuous flow conditions, on the VFD now allows direct access to the dimethylamino functionalized

Chapter 2 Introduction to series of papers 1,5-diketone, 4a. However, low amounts of chalcone, 3a were formed with the 1,5-diketone, depending on the option of control parameters.

R3 R NMe 2 4

H O R1 3a-d (v) (i) N R2 6a Me 2N O R3 R OMe 4

R3 + R1 R4 R2 O H 1 2 (iv) (ii) R N 3 R (iii) 4 R1 R1

R2 5a-d R2 O O

R2 R2 a R1=NH2, R3=NMe2, R2=R4=H

b R1=NH2, R3=Br, R2=R4=H R1 R1 c R1=NH2, R3=H, R2=R4=(CH2)4 4a-c d R =NH , R =OH, R =H, R =OCH 1 2 3 2 4 3

Scheme 2.1 Synthesis of 2,4,6-triarylpyridienes. Reaction conditions: (i) 1:1 equivalent of ketone (1) and aldehyde (2), NaOH (1 eqv.), 80⁰C/RT, PEG300, confined mode VFD, (ii) 2:1 equivalent of ketone (1) and aldehyde (2), NaOH (2 eqv.), 80⁰C, PEG300/

1-propanol, continuous flow mode VFD; (iii) NH4OAc (excess), 100⁰C, PEG300, 25 batch mode ; (iv) 2:1 equivalent of ketone (1) and aldehyde (2), NH4OAc (excess), 80⁰C, PEG300, continuous flow mode VFD; (v) Batch mode, 90%.25

Finally, the 1,5-diketones were cyclised to 2,4,6-triarylpyridines 5 using batch mode processing. Interestingly the 2,4,6-triarylpyridines can also be formed in the VFD under continuous flow conditions in a single pass in the presence of NH4OAc and PEG. This is significant for the vanillin-functionalized triarylpyridine, 5d as it was not possible to isolate the 1,5-diketone precursor.

Organic fluorescent materials have been the subject of intense study for more than a decade because of their rapidly increasing applications. Herein, the utility of the VFD was further developed in gaining access to a series of polysubstituted and N,N′-dimethyl

Chapter 2 Introduction to series of papers containing 2,4,6-trisubstituted pyridines. The choice of the VFD in the present study relates to its ability to scale down under constant shear using the confined mode method. The intense shear arises from the cross vector of centrifugal force and gravity, for a tube rotating at 45⁰ tilted relative to the horizontal position. The synthesis of indanone containing polysubstituted pyridines and N,N′-dimethyl amino containing 2,4,6-triarylpyridines were successfully synthesized in a one-pot reaction in the presence of ammonium acetate and PEG under confined mode of the VFD in moderate yields.

The UV and fluorescence properties of these two series of compounds were investigated and compared in different solvents. This data strongly suggests that strong electron donating groups in the parent aldehyde are a key factor to increasing the fluorescence intensity in polysubstituted pyridine derivatives. On the other hand, this results establishes that the fluorescent intensity is dependent on the parent acetophenone group not bearing strong electron withdrawing groups in N,N′-dimethyl amino containing 2,4,6-triarylpyridines derivatives. The 2D fluorescent plots indicate that the majority of the compounds synthesised show two excitation peak resulting in one emission peak which probably arises from a π–π* and a n–π* electronic transition.

Results published in:

L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston. Optimising a vortex fluidic device for controlling chemical reactivity and selectivity. Scientific Reports, 2013, 3, 2282.

L. Yasmin, P. K. Eggers, B. W. Skelton, K. A. Stubbs and C. L. Raston. Thin film microfluidic synthesis of fluorescent highly substituted pyridines. Green Chemistry, 2014, 16, 3450-3453.

Chapter 2 Introduction to series of papers

Graphical abstract

2.3 Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes

Resorcin[4]arenes and pyrogallol[4]arenes are macrocyclic products formed from the condensation of aldehydes (aliphatic or aromatic) and resorcinol or pyrogallol with 8 or 12 upper rim hydroxyl groups, respectively, which can be used for further chemical elaboration. They have been used in a wide range of applications since their first synthesis (discussed in Chapter 1.3). In traditional synthesis of these macrocycles, reaction time varies from hours to several days, with the nature of the aldehydes requiring specific conditions.

Due to the non-planarity of resorcin[4]arenes and pyrogallol[4]arenes they can exist in many different isomeric forms. The stereochemistry of these molecules is generally defined as the crown (C4v) boat (C2v), chair (C2h), diamond (Cs) and saddle (D2d) arrangements. The relative configurations of the substituents at the methylene bridges can be all cis (rccc), cis-trans-cis (rctc), cis-cis-trans (rcct) and cis-trans-trans (rctt).

However, the chair (C2h) and the crown (C4v) conformers are the main stereoisomers

Chapter 2 Introduction to series of papers and in some specific cases the kinetically favoured chair isomer is converted into the thermodynamically more stable crown isomer after longer reaction times.138

The synthesis of resorcin[4]arenes and pyrogallol[4]arenes involving different aromatic and aliphatic aldehydes using the VFD are described in third paper (Chapter 3.3). The general procedure for the preparation of calix[4]arenes involved treating resorcinol or pyrogallol (1 eqv.) and aldehydes (1 eqv.) in a 20:1 mixture of ethanol and concentrated hydrochloric acid under the continuous flow mode of VFD. This contrasts with earlier work involving typically a 4:1 ratio of solvents and acids, as a traditional batch process.119 Almost all the macrocycles were characterised as their rccc crown (C4v) isomer in this method.

The calix[4]arene macrocycle, synthesised from vanillin and resorcinol was prepared in both the rccc C4v and rctt C2h isomers under continuous flow conditions with the ratio of C4v and C2h being 3:4. Surprisingly, the VFD significantly reduces the reaction time for the preparation of these compounds. This is consistent with the microfluidic platform providing a ‘soft’ form of energy to increase molecular collisions for reactions 17 under diffusion control. Of interest is that the C2h isomer was prepared in 5 days using 211 traditional method processing with no formation of the C4v isomer. The ratio of these stereoisomers could be controlled by changing the different reaction parameters for the

VFD. Furthermore, if the above mentioned mixture of isomers (C4v and C2h) was treated under confined mode of VFD in acidic media, only the C4v isomer was found with this conversion. It could be rationalised that in the continuous flow mode the reaction time (residence time) is short and this time is not sufficient for conversion of the lower symmetry isomer to the thermodynamically more stable C4v isomer.

Results published in:

L. Yasmin, T. Coyle, K. A. Stubbs and C. L. Raston. Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films. Chemical Communications, 2013, 49, 10932-10934.

Chapter 2 Introduction to series of papers Graphical abstract

2.4 Diels-Alder reactions in aqueous medium

Breslow et al. established that Diels–Alder reactions proceed faster (as high as 700- fold) in water than in organic solvents.187 The main difficulty of the reaction in water is the low solubility of materials which is solved by the addition of a suitable alcohol as a co-solvent. In optimized conditions (45° tilt angle and 5000 rpm speed) for the VFD, 9,10-Diels-Alder cycloadducts were formed from different 9-substitute anthracenes and different N-substituted maleimides in high yields in only 30 minutes.

Inside the reaction tube of the VFD both centrifugal and gravitational forces are active at the 45° tilt angle. The intense shear layers in dynamic thin film promote the Diels–Alder reaction which results in higher yields of cycloadduct product. The rotating speed of the VFD has drastic effects on accelerating this reaction. In the first paper (Chapter 3.1) higher speeds favour the progress of organic reactions but surprisingly here it was found that changing the speed had little effect on the reaction outcome. This potentially was explained by the solvent accessible surface between the initial stage of the reaction and the transition state.

Chapter 2 Introduction to series of papers Results published in:

L. Yasmin, K. A. Stubbs and C. L. Raston. Vortex fluidic promoted Diels-Alder reactions in aqueous medium. Tetrahedron Letters, 2014, 55(14), 2246-2248.

Graphical abstract

O 2 R N

O O H O, EtOH 2 2 N R + 500C

1 1 R O R

R1 = R2 = various examples

Chapter 3 Series of papers 3. Series of Papers

3.1 Optimising a vortex fluidic device for controlling chemical reactivity and selectivity

47 OPEN Optimising a vortex fluidic device for

SUBJECT AREAS: controlling chemical reactivity and FLOW CHEMISTRY METHODOLOGY selectivity SUSTAINABILITY Lyzu Yasmin1, Xianjue Chen1, Keith A. Stubbs2 & Colin L. Raston3 CHEMICAL ENGINEERING

1Centre for Strategic Nano-Fabrication, School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, 2 Received Crawley, W.A. 6009, Australia, School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, 3 11 April 2013 Crawley, W.A. 6009, Australia, School of Chemical and Physical Sciences, Flinders University, Bedford Park, S.A. 5042, Australia. Accepted 9 July 2013 A vortex fluidic device (VFD) involving a rapidly rotating tube open at one end forms dynamic thin films at Published high rotational speed for finite sub-millilitre volumes of liquid, with shear within the films depending on the 25 July 2013 speed and orientation of the tube. Continuous flow operation of the VFD where jet feeds of solutions are directed to the closed end of the tube provide additional tuneable shear from the viscous drag as the liquid whirls along the tube. The versatility of this simple, low cost microfluidic device, which can operate under confined mode or continuous flow is demonstrated in accelerating organic reactions, for model Diels-Alder Correspondence and dimerization of cyclopentadienes, and sequential aldol and Michael addition reactions, in accessing unusual requests for materials 2,4,6-triarylpyridines. Residence times are controllable for continuous flow processing with the viscous drag should be addressed to dominating the shear for flow rates .0.1 mL/min in a 10 mm diameter tube rotating at .2000 rpm. C.L.R. (colin.raston@ flinders.edu.au) anipulating fluids in micrometre dimensions is central to microfluidic lab-on-a-chip devices which have a plethora of applications ranging from microanalysis, molecular biology, microelectronics, and to new territories in chemistry and biochemistry1,2. Microfluidics also encompasses dynamic fluidic thin films M 3–18 generated centrifugally by passing liquids over rotating surfaces, as in spinning disc processors (SDPs) and horizontally aligned rotating tube processors (RTPs) with open ends18–24. These processors are effective in controlling chemical reactions3–13,22, probing the structure of self organised systems14, and exfoliation and scroll- ing of graphite and hexagonal boron nitride (h-BN)3,18–24. However, the volumes of liquid required for maintaining constant shear intensity in the fluids flowing over the rotating surfaces, coupled with finite residence times and high cost of construction, can limit the scope of their applications. Herein we report the details of a low cost vortex fluidic device (VFD) which has a rapidly rotating tube open at one end, where at high rotational speed, intense shear is generated in the resulting thin films for finite sub-millilitre volumes of liquid, depending on the speed and orientation of the tube, and other operating parameters. This is the ‘confined mode’ of operation of the VFD. It can also operate under the ‘continuous flow mode’ with jet feeds delivering liquid into the rotating tube where additional shear is generated in the thin films from the viscous drag as the liquid whirls along the tube. We have recently established that the VFD is effective in exfoliating graphite and h-BN25,26, controlling the decoration of palladium nano-particles on carbon nano-onions arising from the high mass transfer of hydrogen gas27 and also palladium nano-particles on graphene28, disassembling self organised molecular capsules14,29, the synthesis of superparamagnetic magnetite nanoparticles embedded in polyvinylpyrrolidone followed by entrapping microalgal cells within this material, and similarly in entrapping them in graphene oxide30,31. The details of the VFD and the different types of shear regimes are now reported using selected organic reactions, initially for Diels-Alder dimerization of cyclopentadienes in optimising the operational parameters of the VFD, then sequential aldol condensation and Michael addition reactions, in gaining direct access to unusual 2,4,6-triarylpyridines which are not possible or inherently difficult and/or of limited practical convenience using traditional batch processing. Overall, the results establish dramatic control of reactivity and selectivity using the VFD, which also further highlights the versatility of the device. Continuous flow devices can facilitate translation of small scale research production to industrial production, minimise waste and energy usage, and can be inherently safer32. These devices include SDP and RTP which overcome the anisotropic thermal environment, and the poor mass and heat transfer observed using traditional batch (flask) processing which can lead to mixtures of products9. The waves and ripples generated on the surface

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 1 www.nature.com/scientificreports of dynamic thin films in SDP and RTP break down surface tension the viscous drag as for the SDP and RTP, as well as a contribution resulting in high mass transfer14,15, and the thinness of the films from a combination of centrifugal force with gravity, for operating at ensures rapid heat transfer between the liquid and rotating sur- tilt angles .0u, as an additional advantage beyond the SDP and RTP, face10,16. SDP has feed jets directed close to the centre of a rapidly along with the ability to use smaller volumes of liquid, and a much rotating disc where there is intense micro-mixing, with residence lower cost of construction. Another advantage of VFD is that it can times of typically less than a second, depending on the size of the also operate in a so-called confined mode for a finite volume of disc, spinning speed, surface texture of the disc itself, viscosity of liquid, for extending the shearing time, where the instability of the liquid and flow rates10. With respect to applications in organic syn- thin films arises exclusively from a combination of centrifugal force thesis, the SDP has been used to isomerize a-pinene7, control poly- and gravity25. merization reactions3,6,8, and prepare 1,5-diketones as an entry to 2,4,6-triaryl pyridines9. Intriguingly, for the latter, several passes Results are required to move beyond the chalcone intermediate to form The prototype of the VFD presented herein operates with a 10 mm significant quantities of the desired 1,5-diketone9. The RTP has jet diameter tube, for speeds up to 10,000 rpm and temperatures up to feeds delivering solutions intensely mixed at one end to go through 200uC. Overall the device has several reproducible operating para- the rapidly rotating tube, with the product collected at the other meters including rotating speed, tilt angle h, and flow rates, along end18–24. Here the residence times can be minutes, depending on flow with operating parameters for traditional batch operated reactions, rates and the length of the tube. such as varying the temperature and concentration of reactants. To overcome limitations in these devices and introduce more To gain insight into the average film thickness for steady state flexibility in parameters, the new vortex fluidic device (VFD) was conditions, we determined the height of the thin film in the tube, designed to operate in the same horizontal position as the RTP, as and thus the internal area of liquid coverage, for a fixed volume of well as being able to operate at different angles, defined by the tilt liquid (Figure 1b). For example, the average thickness of the liquid angle, h, with a closed end of the tube and jet feeds for delivering film for 1 mL of water in the 10 mm tube inclined at 45u and rotating liquids and any gases from the other end, which is where the result- speed at 7000 rpm is ,230 mm. We found that the shape of the film ing processed liquid departs under continuous flow operation is quasi-parabolic and where the vortex extends to the base of the (Figure 1a). Shear in the thin films formed in the VFD arise from tube for high rotating speeds, it approximates to a uniform film

Figure 1 | Vortex fluidic device (VFD). (a) Cross section showing the components of the device. (b) Average film thickness (mm) versus tilt angle h, which was determined mathematically from the surface coverage of the film for 1 mL of water containing a low concentration of dye, in a standard 10 mm NMR tube with distances along its length marked externally to establish the upper level of the liquid. (c) Photographs showing the film of liquid developed for different speeds, for 3 mL of an aqueous solution, for h 5 45u, with 3000 rpm showing a quasi-parabolic film.

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 2 www.nature.com/scientificreports

(Figure 1c). On the other hand if the liquid does not form a complete speed, for 1 hour processing, from ca 2000 rpm to 10,000 rpm vortex to the bottom of the tube, the fluid flow becomes more (Figure 2c). Operating speeds $2000 rpm under this confined mode complex. ensures that the resulting vortex is maintained to the base of the tube, To understand the effect of the VFD on molecular reactions, we for a more uniform shear present in the thin film, which is consistent investigated the dimerization of neat cyclopentadiene and methylcy- with our initial observations (Figure 1b). clopentadiene for different rotating speeds and tilt angles, at room To investigate VFD under continuous flow we used methylcyclo- temperature, under confined mode (Figure 2) and continuous flow pentadiene to overcome the evaporative loss of cyclopentadiene at mode (Figure 3), respectively. In confined mode, fixing the speed at room temperature, and found that the percent dimerization 7000 rpm, the processing time at 1 hour and varying the tilt angle for increases dramatically relative to the confined mode. For example, 0.2 mL of cyclopentadiene results in an increase in percent conver- 0.2 mL of methylcyclopentadiene at room temperature for 1 hour sion to the dimer, for h . 0 (Figure 2a). As h increases the percent with h 5 45u for the tube rotating at 7000 rpm results in 0.75% dimerization increases to a plateau at ca 45u then decreases before dimerization (compared with 0.34% for the static control) whereas increasing again as h reaches 90u. Given the practical inconvenience for a single pass under continuous flow conditions for the 15 cm long of operating at this angle, especially when operating under continu- tube, with h 5 45u for a flow rate of 0.1 mL/min, there is 1.9% ous flow, the optimum shear for confined mode was set at h 5 45u, dimerization, for which the residence time on the tube is approxi- which corresponds to the optimum angle for exfoliation of graphite mately 12 minutes. For a low constant flow rate of 0.1 mL/min with and h-BN, and also for continuous flow dimerization conditions at the tube rotating at 7000 rpm, the percent dimerization increases for low flow rates (see below)25. For 7000 rpm and h 5 45u, for the same increasing speed, although this is small for h 5 0u (Figure 3a). As h volume of liquid, there is an increase in percent dimerization over increases the dimerization increases up to 45u, then decreases up to time relative to the static control and for h 5 0u (Figure 2b). At h 5 0u 60u, followed by progressive increases at 75 and 90u, which is con- the liquid will rotate close to the same speed as the tube, with no sistent with the variation in dimerization observed in the confined shear, and consistent with this is that the outcome is the same as the mode. static control sample, with 2.5% conversion after 3 hours, compared Dimerization of methylcyclopentadiene under different flow rates, with 6.8% conversion in the VFD. For comparison, agitation using with the tube rotating at 7000 rpm, varies dramatically for lower flow conventional rapid magnetic stirring results in some additional rates (Figure 3b). At the maximum flow rate (1.0 mL/min) there is dimerization, increasing from 2.5% to 3.6% conversion for the same essentially no difference in the percent conversion with variation in period. For h 5 45u, the percent dimerization increases for increasing h, but significant differences develop in tracking to the lowest flow

Figure 2 | Confined mode dimerization of cyclopentadiene (CpH). Relative percent dimerization of (a) CpH versus tilt angle h at 7000 rpm for 1 hour, (b) CpH versus time at 7000 rpm, and (c) CpH versus speed at h 5 45u for 1 hour.

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 3 www.nature.com/scientificreports

Figure 3 | Continuous flow dimerization of methylcyclopentadiene (MeCpH). Relative percent dimerization of (a) MeCpH at various speeds for different h values, at a flow rate of 0.1 mL/min, and (b) MeCpH with varying flow rate at different h values at 7000 rpm, for a single pass through the VFD. rate (0.1 mL/min) where the conversion increases as h increases to there is a larger amount of the compound, especially at a low flow 45u, decreases as it approaches 60u then increases again towards 90u. rate. This again reflects a different shear regime at this angle, con- For h 5 45u there is a four-fold increase in dimerization relative to h sistent with what has been identified in the dimerization of methyl 5 0u, and effectively establishes the contribution from the shear cyclopentadiene. However, the confined mode operation of the VFD associated with viscous drag as the liquid moves along the horizontal is effective in preparing the chalcones 3a–d in high yield. Thus the tube (h 5 0u), and the additional contribution to shear established in choice of continuous flow versus confined mode is another para- the confined mode (see above) for h . 0u. At low flow rates the film meter in gaining control over the outcome of the reactions. thickness is expected to be smaller than at high flow rates for the same Interestingly the 2,4,6-triarylpyridines 5a–d can also be formed in speed, and with thicker films the overall contribution of the shear the VFD under continuous flow conditions in a single pass in the from the viscous drag will be reduced. The increase in percent con- presence of NH4OAc (Figure 4a, reaction iv). This is particularly version at high h ($75u) then establishes a different shear regime, important for 5d given that it was not possible to make the 1,5- albeit of less practical convenience where the mass of the liquid has to diketone precursor, 4d, using methods (ii) and (iii) (Figure 4a). move up the side of the tube against gravity. The low conversions 2,4,6-Triarylpyridines are accessible using SDP but the short res- observed at low speeds for higher h values relates to these thicker idence time necessitates several passes through the microfluidic films and the resultant less shear as the liquid moves along and up the device, with less control over the product distribution9. They are also tube in overcoming the effect of gravity. accessible in a one step process in the presence of NH4OAc using We have translated the optimised conditions of these dimerization microwave irradiation33, but this is not immediately scalable proces- reactions to investigate confined and continuous flow synthesis of sing, and the energy usage using microwave heating is questionable34. 2,4,6-triarylpyridines (Figure 4a). These are formed via an aldol condensation reaction to give 3a–d, followed by a Michael addition to Discussion give 4a–c (Figure 4). In some cases there is a need to gain control over The VFD has different shear regimes in the thin films. For the con- competing reactions, as in the undesirable Schiff base condensation fined mode of operation, the shear depends on the tilt angle h of the coupled with aldol condensation (compound 6a), which is a favoured rapidly rotating tube, which is greatest at 45u and 90u, and the speed product using batch processing in attempting to prepare the 1,5- of the tube. This was established by the increase in dimerization of diketone 4a via the chalcone 3a. This unwanted product arises from cyclopentadiene relative to controls (h 5 0u, no agitation or stirring poor heat and mass transfer which is overcome using SDP, but of the liquid). For the continuous flow mode, the viscous drag dom- requires multiple passes because of the short residence time (,1 inates the shear for flow rates at 1.0 mL/min, and for flow rates second for a 10 cm disc)9. A single pass, under continuous flow approaching 0.1 mL/min the different shear established for the con- conditions, on the VFD now allows direct access to 4a, albeit with fined mode also become important, which has been established by low amounts of chalcone formation, depending on the choice of the increase in dimerization of methylcyclopentadiene relative to the control parameters (Figure 4b). At low flow rate (0.1 mL/min) the same controls. percent yield is higher than at corresponding high flow rates (1 mL/ The increase in shear, as judged by the increase in dimerization of min) which is expected due to the longer residence time, but high the cyclopentadienes, for h up to 45u, then a decrease before an flow rate reduces the relative amount of chalcone being formed. The increase as h approaches 90u, defines different shear regimes corres- amount of chalcone is minimal for h 5 0 and 90u, whereas at 45u ponding to different orientations of the centrifugal force relative to

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 4 www.nature.com/scientificreports

Figure 4 | Synthesis of 2,4,6-triarylpyridienes. (a) Reaction conditions: (i) 151 equivalent of ketone (1) and aldehyde (2), NaOH (1 eqv.), 80uC (or room temperature for 3b and 3c), PEG300, confined mode VFD, h 5 45u, 7000 rpm, 30 mins, percentage yield: 52% 3a, 65% 3b, 61% 3c, 20% 3d; (ii) 251 equivalent of ketone (1) and aldehyde (2), NaOH (2 eqv.), 80uC, PEG300 (or 1-propanol for 4a), continuous flow mode VFD, h 5 0u, 7000 rpm, 9 0.1 mL/min, percentage yield: 43% 4a, 48% 4b, 45% 4c; (iii) NH4OAc (excess), 100uC, PEG300, batch mode ; percentage yield 94% 5a, 78% 5b, 91% 5c; (iv) 251 equivalent of ketone (1) and aldehyde (2), NH4OAc (excess), 80uC, PEG300, continuous flow mode VFD, h 5 45u, 7000 rpm, 0.5 mL/min, percentage yield: 38% 5a, 21% 5b, 19% 5c, 45% 5d; (v) Batch mode, 90% 6a9. (b) Product distribution for a 251 reaction of 1 and 2, in generating a mixture of 3a and 4a. gravity, for which the fluid dynamics is presumably complex. The microfluidic device for improving the outcome of chemical reactions. findings provide a basis for understanding the outcome of recent This coupled with the ability to scale down to sub-millilitre volumes applications of the VFD operating under confined mode, where in the confined mode or scale up under continuous flow mode while the optimum tilt angle approximated to 45u. This includes the ‘top maintaining intense shear allows for controlled chemical reaction down’ exfoliation of laminar material25,26, the ‘bottom up’ growth of conditions to be achieved. There is potential for application of the nano-particles27,28, disassembly of self organised systems14,29, and VFD in a myriad of functional group transformations, with hierarch- entrapping microalgal cells30,31. The results for the continuous flow ical control, including reactions of gases with liquids, in taking synthesis are consistent with the synthesis of superparamagnetic advantage of the high mass transfer of gases at the dynamic interface nanoparticles for h at 0u for a flow rate of 1 mL/min30, noting that between the two states. A potential limitation of the VFD is continu- the tilt angle under continuous flow becomes important for much ous flow operation for highly viscous liquids and/or where the prod- slower flow rates, especially approaching 0.1 mL/min. uct gelates which may clog the outlet system. The shear in the confined and continuous flow modes is effective The VFD is modular and can be readily modified, in changing the in enhancing the chemical reactions, in providing a ‘soft’ form of nature of the tube, with surface texture features for increasing the energy to increase molecular collisions for reactions under diffusion intensity of micro-mixing, and covalent attachment, in controlling control. The increase in percent conversion of the cyclopentadienes the contact angle of the surface (hydrophobic/hydrophilic balance) is possible without heating the samples, and for the formation of the to change the viscous drag and thus the shear intensity. The VFD can 2,4,6-triarylpyridines the ability to circumvent the formation of the also incorporate field effects, including standard light sources and Schiff base, compound 6a, establishes the ability to gain control over lasers, and has high throughput processing capabilities for devel- kinetic verses thermodynamic product. Intense micromixing and oping libraries of nanomaterials and organic compounds. Several associated shear here also allows direct access to amine substituted reactions can potentially be telescoped within a single platform, or chalcones and 1,5-diketones, without the need to prepare the corres- sequential platforms, with the ability to carry out reactions in an inert ponding nitro-compounds35, for then reduction of the functional atmosphere using a gas feed or by placing the small unit in a con- groups post-aldol and Michael addition reactions, and also forma- trolled atmosphere glove box, and properties of liquids under intense shear can also be studied for small volumes. tion of the 2,4,6-trialylpyridine. The above cyclopentadiene Diels-Alder reactions and the ability to Methods use the VFD to control reactivity and selectivity in the formation of 1Hand13C NMR spectra were recorded on a Varian NMR spectrometer at 400 and 2,4,6-triarylpyridines, establishes the utility of using the inexpensive 100 MHz respectively. The VFD was constructed at The University of Western

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 5 www.nature.com/scientificreports

Australia, and all experiments used a 10 mm NMR tube, 15 cm in length, which was 20. Fang, J., Guo, Y., Lu, G., Raston, C. L. & Iyer, K. S. Enhancement of quantum yield 31 31 capped in the confine mode dimerization studies of 0.2 mL of freshly distilled of LaPO4:Ce :Tb nanocrystals by carbon nanotube induced suppression of cyclopentadiene. For dimerization studies of under continuous flow mode, freshly the1-dimensional growth. Dalton Trans. 40, 3122–3124 (2011). distilled methylcyclopentadiene was kept in an ice bath prior to use, and the liquid 21. Dev, S., Iyer, K. S. & Raston, C. L. Nanosized drug formulations under microfluidic was collected after steady state flow from the tube. The percent conversions for both continuous flow. Lab Chip 11, 3214–3217 (2011). studies were determined using 1H NMR. For the confined mode synthesis of the 22. Lodha, H., Jachuck, R. & Singaram, S. S. Intensified biodiesel production using a chalcones (3), a mixture of p-aminoacetophenone (1) (1 mmol), sodium hydroxide rotating tuber. Energy Fuels 26, 7037–7040 (2012). (1 mmol) and benzaldehyde (2) (1 mmol) in 2 mL PEG was spun in a capped tube at 23. Dev, S., Prabhakaran, P., Filgueira, L., Iyer, K. S. & Raston, C. L. Microfluidic 7000 rpm, 45u degree tilt angle at 80uC (for 3a and 3d) or ambient temperature (for 3b fabrication of cationic curcumin nanoparticles as an anti-cancer agent. Nanoscale and 3c) for 30 minutes. Water (25 mL) was then added and the resulting yellow 4, 2575–2579 (2012). precipitate collected and dried in vacuo. For continuous flow synthesis of 1,5-diones 24. Dev, S., Toster, J., Prasanna, V., Fitzgerald, M., Iyer, K. S. & Raston, C. L. (4), p-aminoacetophenone (1) (1 mmol) and hydroxide (2 mmol) in PEG 300 Suppressing regrowth of microfluidic generated drug nanocrystals using (1 mL) was directed through one jet feed, with the other a solution of benzaldehyde polyelectrolyte coatings. RSC Adv. 3, 695–698 (2013). 2 ( ) (1 mmol) in PEG 300 (1 mL). Both solutions were then passed through the VFD 25. Chen, X., Dobson, J. F. & Raston, C. L. Vortex fluidic exfoliation of graphite and using continuous flow mode; 80 C, 7000 rpm, 0 degree tilt angle and 0.1 mL/min u boron nitride. Chem. Commun. 48, 3703–3705 (2012). flow rate. Water was added to the processed liquid affording a yellow precipitate as 26. Wahid, M. H., Eroglu, E., Chen, X., Smith, S. M. & Raston, C. L. Functional multi- mixture of 1,5-diketone (4) and chalcone (3). Similarly excess NH OAc (400 mg) was 4 layer graphene - algae hybrid material formed using vortex fluidics. Green Chem. used in place of NaOH, to afford the 2,4,6-triarylpyridine (5) directly. 15, 650–655 (2013). 27. Yasin, F. Md. et al. Microfluidic size selective growth of palladium nano-particles 1. Whitesides, G. M. The origins and the future of microfluidics. Nature 442, on carbon nano-onions. Chem. Commun. 48, 10102–10104 (2012). 368–373 (2006). 28. Chen, X. et al. Non-covalently modified graphene supported ultrafine 2. Y. Yeo, L. Y., Chang, H. C., Chan, P. P. Y. & Friend, J. R. Microfluidic devices for nanoparticles of palladium for hydrogen gas sensing. RSC Adv. 3, 3213–3217 bioapplications. Small 7, 12–48 (2011). (2013) 3. Cheong, S. I. & Choi, K. Y. J. Melt polycondensation of poly(ethylene 29. Martin, A. D., Boulos, R. A., Hubble, L. J., Hartlieb, K. J. & Raston, C. L. terephthalate) in a rotating disk reactor. Appl. Polym. Sci. 58, 1473–1483 (1995). Multifunctional water-soluble molecular capsules based on p-phosphonic acid 4. Boodhoo, K. V. K. & Jachuck, R. J. Process intensification: spinning disk reactor calix[5]arene. Chem. Commun. 47, 7353–7355 (2011). for condensation polymerization. Green Chem. 2, 235–244 (2000). 30. Eroglu, E, D’Alonzo, N. J., Smith, S. M. & Raston, C. L. Vortex fluidic entrapment 5. Boodhoo, K. V. K. et al. Classical cationic polymerization of styrene in a spinning of functional microalgal cells in a magnetic polymer matrix. Nanoscale 5, disc reactor using silica-supported BF3 catalyst. J. Appl. Polym. Sci. 101, 8–19 2627–2631 (2013). (2006). 31. Wahid, M. H., Eroglu, E., Chen, X., Smith, S. M. & Raston, C. L. Entrapment of 6. Vicevic, M., Novakovic, K., Boodhoo, K. V. K. & Morris, A. J. Kinetics of styrene Chlorella vulgaris cells within graphene oxide layers. RSC Adv. 3, 8180–8183 free radical polymerisation in the spinning disc reactor. Chem. Eng. J. 135, 78–82 (2013). (2008). 32. Seeberger, P. H. Scavengers in full flow. Nature Chem. 1, 258–260 (2009). 7. Vicevic, M., Boodhoo, K. V. K. & Scott, K. Catalytic isomerisation of a-pinene 33. Yin, G., Liu, Q., Ma, J. & She, N. Solvent- and catalyst-free synthesis of new oxide to campholenic aldehyde using silica-supported zinc triflate catalysts. II. hydroxylated trisubstituted pyridines under microwave irradiation. Green Chem. Performance of immobilized catalysts in a continuous spinning disc reactor. 14, 1796–1798 (2012). Chem. Eng. J. 133, 43–57 (2007). 34. Moseley, D. D. & Kappe, C. O. A critical assessment of the greenness and energy 8. Moghbeli, M. R., Mohammadi, S. & Alavi, S. M. Bulk free-radical polymerization efficiency of microwave-assisted organic synthesis. Green Chem. 13, 794–806 of styrene on a spinning disc reactor. J. Appl. Polymer Sci. 113, 709–715 (2009). (2011). 9. Smith, N. M., Corry, B., Iyer, K. S., Norret, M. & Raston, C. L. A microfluidic 35. Tamami, B. & Yeganeh, H. Synthesis and characterization of novel aromatic platform to synthesise a G-quadruplex binding ligand. Lab Chip 9, 2021–2025 polyamides derived from 4-aryl-2,6-bis(4-aminophenyl)pyridines. Polymer 42, (2009). 415–420 (2001). 10. Cafiero, L. M., Baffi, G., Chianese, A. & Jachuck, R. J. J. Process Intensification: Precipitation of barium sulfate using a spinning disk reactor. Ind. Eng. Chem. Res. 41, 5240–5246 (2002). 11. Tai, C. Y., Tai, C. T., Chang, M. H. & Liu, H. S. Synthesis of magnesium hydroxide and oxide nanoparticles using a spinning disk reactor. Ind. Eng. Chem. Res. 46, Acknowledgements 5536–5541 (2007). Support of this work by the Australian Research Council and Centre for Microscopy, 12. Iyer, K. S., Raston, C. L. & Saunders, M. Continuous flow nano-technology: Characterisation and Analysis at the University of Western Australia is greatly manipulating the size, shape, agglomeration, defects and phases of silver acknowledged. nano-particles. Lab Chip 7, 1800–1805 (2007). 13. Chan, B. C. Y. et al. Light-driven high-temperature continuous-flow synthesis of TiO nano-anatase. Chem. Eng. J. 211–212, 195–199 (2012). Author contributions 2 X.C. carried out fluid flow experiments, L.Y. carried out the organic reactions, K.A.S. and 14. Iyer, K. S., Norret, M., Dalgarno, S. J., Atwood, J. L. & Raston, C. L. Loading molecular hydrogen cargo within viruslike nanocontainers. Angew. Chem. Int. Ed. C.L.R. designed the organic synthesis experiments and wrote the paper, all authors reviewed 47, 6362–6366 (2008). the manuscript, and C.L.R. designed the micofluidic platform and coordinated the research. 15. Aoune, A. & Ramshaw, C. Process intensification: heat and mass transfer characteristics of liquid films on rotating disks. Int. J. Heat Mass Transfer 42, Additional information 2543–2556 (1999). Supplementary information accompanies this paper at http://www.nature.com/ 16. Ghiasy, D., Boodhoo, K. V. K. & Tham, M. T. Thermographic analysis of thin scientificreports liquid films on a rotating disc: Approach and challenges. Appl. Thermal Eng. 44, 39–49 (2012). Competing financial interests: The authors declare no competing financial interests. 17. Chen, X., Boulos, R. A., Dobson, J. F. & Raston, C. L. Shear induced formation of How to cite this article: Yasmin, L., Chen, X., Stubbs, K.A. & Raston, C.L. Optimising a carbon and boron nitride nano-scrolls. Nanoscale 5, 498–502 (2013). vortex fluidic device for controlling chemical reactivity and selectivity. Sci. Rep. 3, 2282; 18. Fang, J., Guo, Y., Lu, G., Raston, C. L. & Iyer, K. S. Instantaneous crystallization of DOI:10.1038/srep02282 (2013). ultrathin one-dimensional fluorescent rhabdophane nanowires at room temperature. Green Chem. 13, 817–819 (2011). This work is licensed under a Creative Commons Attribution 3.0 Unported license. 19. Fang, J. et al. Sequential microfluidic flow synthesis of CePO4 nanorods decorated To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0 with emission tunable quantum dots. Lab Chip 10, 2579–2582 (2010).

SCIENTIFIC REPORTS | 3 : 2282 | DOI: 10.1038/srep02282 6 Chapter 3 Series of papers 3.2 Thin film microfluidic synthesis of fluorescent highly substituted pyridines

54 Green Chemistry

View Article Online COMMUNICATION View Journal

Thin film microfluidic synthesis of fluorescent highly substituted pyridines† Cite this: DOI: 10.1039/c4gc00881b Received 14th May 2014, Lyzu Yasmin,a Paul K. Eggers,a,c Brian W. Skelton,b Keith A. Stubbsa and Accepted 9th June 2014 Colin L. Raston*c DOI: 10.1039/c4gc00881b

www.rsc.org/greenchem

A facile, one pot method for the synthesis of a series of polysubsti- use of pyridinium salts, which are derived from the reaction of tuted and 2,4,6-trisubstituted pyridines using a thin ﬁlm vortex an halogenated-methyl ketone with pyridine. Such one-pot ﬂuidic device has been developed, with the compounds obtained reactions involve acetophenone, an aryl aldehyde, and

in good yield following simple purification procedures. Changes in ammonium acetate (NH4OAc). They include reactions under – fluorescence intensity and excitation/emission parameters are solventless conditions,12 the use of microwave irradiation,13 15 demonstrated through variation of functional groups, without NaOH in PEG,16,17 catalytic amounts of acetic acid,18 Preyssler- 19 20 significantly impacting on the synthetic yield. type heteropolyacid H14[NaP5W30O110], bismuth triflate and a Brønsted acidic ionic liquid.21 Although a variety of Development of new fluorescent organic compounds with high approaches toward gaining access to substituted pyridines functionality has been the subject of intense study for more have been established, versatile and efficient methods for the than a decade because of rapidly increasing applications of construction of the pyridine core which are compatible with organic fluorescent materials for electroluminescence (EL), various functional groups remain highly desirable. Given the 1–3 dye-lasers, sensors, probes, and phototherapeutic agents. aforementioned chemical and pharmacological significance of Triarylpyridines are structurally related to the symmetrical the substituted pyridines, the synthesis of such types of mole- triaryl-thiopyrylium, triarylselenopyrylium, and triaryl-telluro- cules is becoming an attractive area of research, in diverting pyrylium photosensitizers, which have been recommended for efforts to develop simple less waste generating routes for 4 photodynamic cell specific cancer therapy. their syntheses by further applying the principles of green Also noteworthy is that the substituted pyridyl heterocyclic chemistry.22 Published on 09 June 2014. Downloaded by University of Western Australia 19/06/2014 10:47:29. core is an extensive sub-unit seen in numerous natural pro- An alternative strategy in minimizing the generation of by- 5,6 ducts and is a versatile moiety in coordination chemistry, products/waste, is the use of process intensification strategies, as well as in supramolecular chemistry due to its ability to beyond the use of solventless and microwave processing, as in π 7–9 engage in -stacking. This provides a compelling reason to dynamic thin films, which can allow for the gaining control of ffi explore alternative, more e cient and more benign methods formation of the kinetic favoured product over the thermo- for the synthesis of such heterocyclic compounds. Tradition- dynamic favoured product.23 In the present study the process ally these compounds have been prepared through the reaction intensification device of choice is a vortex fluidic device (VFD), α β of N-phenacylpyridinium salts with , -unsaturated ketones, where intense shear is present for the device operating in both 10,11 which is better known as the Kröhnke synthesis. More the so called continuous flow and confined modes of oper- recently one-pot reactions have been developed for the syn- ation, which have recently been studied in detail.24 The thin thesis of some triarylpyridines, in a drive to improve the film VFD is emerging as a versatile device for a diverse range associated green chemistry metrics, especially in avoiding the of applications, including exfoliation of laminar material,25,26 controlled growth of nano-particles,27,28 disassembly of self- 29 30 a organised systems, preparing mesoporous silica entrapping School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling 31,32 Highway, Crawley, WA 6009, Australia microalgal cells, and in controlling reactivity and selecti- bCentre for Microscopy, Characterisation and Analysis, University of Western vity in organic synthesis, notably in accelerating Diels–Alder Australia, 35 Stirling Highway, Crawley, WA 6009, Australia reactions,33 stereochemical control of the synthesis of calixar- c School of Chemical and Physical Sciences, Flinders University, Bedford Park, enes,34 and the synthesis of amino functionalized 2,4,6-triaryl- SA 5042, Australia. E-mail: [email protected] pyridines, where formation of the thermodynamically favoured †Electronic supplementary information (ESI) available. CCDC 972818. For ESI ff 24 and crystallographic data in CIF or other electronic format see DOI: 10.1039/ Schi base adduct of the chalcone is avoided. For the latter, c4gc00881b the same outcome is possible when using a related spinning

This journal is © The Royal Society of Chemistry 2014 Green Chem. View Article Online

Communication Green Chemistry

disc microfluidic platform, albeit due to the limited residence Table 1 Synthesis of various polysubstituted pyridines 3a–e in PEG300 time of the liquid on the surface of the rapidly rotating disc as using the VFD operating at 7000 rpm and 45° tilt angle at 100 °C for fi a strictly continuous flow process, several passes are required 30 minutes in the con ned mode 35 for a similar outcome relative to using the VFD. Fluorescence Herein, we further develop the utility of the VFD in gaining access to a series of poly-substituted and N,N-dimethyl con- Yield CH3CN DMSO Entry R R R (%) λ /λ (nm) λ /λ (nm) taining 2,4,6-trisubstituted pyridines, and investigate the 1 2 3 exc em exc em fluorescent properties of these new molecules. The choice of 3a OH H H 67 345/365 340/370 3b – – the VFD in the present study relates to its ability to scale down H C4H4 65 240/380 350/385 3c OH OCH H 62 340/365 340/365 under constant shear using the confined mode, in further 3 3d OCH3 OH H 68 340/365 340/365 mapping out the novel capabilities of the microfluidic plat- 3e (CH3)2N H H 60 340/475 340/480 form in general, as well the potential to develop a robust benign method for gaining access to a diverse range of fluorescence molecules. Previously we reported two synthetic strategies for preparing Table 2 Synthesis of various 2,4,6-triarylpyridines 6a–e in PEG300 2,4,6-triaryl pyridines. The first involved two steps, initially using the VFD operating at 7000 rpm and 45° tilt angle at 100 °C for 30 minutes in the confined mode forming the 1,5-diketone via a sequential aldol and Michael addition reactions using the VFD in the continuous flow Fluorescence mode. The second method was a one step method using the CH3CN DMSO VFD, as a three component condensation in the presence of Entry R R Yield (%) λ /λ (nm) λ /λ (nm) 24 1 2 exc em exc em NH4OAc, also in the continuous flow mode. We have now 6a — expanded these strategies through a study involving the NO2 H 66 330/460 6b HNO59 —— three component condensation involving 1-indanone 1 as the 2 6c OCH3 H 53 330/435 340/440 2a–e 6d ketone with various aldehydes . This gains access to poly- CH3 H 62 340/450 340/460 6e substituted pyridines 3a–e under the confined mode of oper- NH2 H 51 330/445 330/465 ation of the VFD, where the intense shear arises from the cross vector of centrifugal force and gravity, for a tube rotating at 45° findings further highlight the versatility of the VFD in control- tilted relative to the horizontal position. ling chemical reactions which operate beyond conventional diffusion control. In principle, the confined mode lends itself to robotic control for scaling up for a large number of sequential reactions of small aliquots of a reacting liquid. The literature suggests that N,N-dimethylamino-containing triarylpyridines are potentially efficient fluorophores,2 and accordingly we also targeted the synthesis of 2,4,6-triarylpyri-

Published on 09 June 2014. Downloaded by University of Western Australia 19/06/2014 10:47:29. dines using the three component condensation for 4-(dimethylamino)benzaldehyde 4 with different acetophenones 5a–e. Using the method established for the preparation of 3a–e In a typical procedure for the synthesis of 3(a–e), 1-indanone 1 we found that this confined mode method using the VFD was (1 mmol), the aldehyde 2a–e (0.5 mmol) and NH OAc 4 also suitable for the preparation of 6a–e, which were obtained (2 mmol) in PEG300 (1 mL) were treated in the confined mode in good yield (Table 2). of VFD at 100 °C for 30 minutes. As a control the reaction was also carried out in a round bottom flask with a stirrer bar under the same reaction conditions and no product formation was observed, as determined using thin layer chromatography. The yields of the reactions undertaken using the VFD were good (Table 1) with little to no by-products observed. Also the scope of the reaction regarding the different aldehydes was found to be excellent, with a variety of different compounds prepared. Of note is that using this three component system in the continuous flow mode of the VFD resulted in low yields, in consequence of the limited residence time of the liquid in the The crystal structure of 6d was also established using single tube for less reactive aldehydes/ketones in the presence of crystal diffraction data, as a representative of the atom-to-atom

NH4OAc. Thus while continuous flow mode of the VFD has connectivity, but more importantly to establish the orientation been used previously for the preparation of other 2,4,6-triaryl- of the planar aromatic rings relative to the central pyridine pyridines,24 it is not applicable for the present series of com- ring (Fig. 1). Indeed the aromatic rings are essentially co- pounds here and those discussed below, and the synthetic planar, as would be expected for the maximum overlap of elec-

Green Chem. This journal is © The Royal Society of Chemistry 2014 View Article Online

Green Chemistry Communication

> 6b in acetonitrile. In DMSO the fluorescent intensity of 6c was enhanced over acetonitrile whilst 6d and 6e were mildly quenched. This data establishes that the fluorescent intensity is dependent on the parent acetophenone group not bearing strong electron withdrawing groups. Also, the 3D fluorescent plots (see ESI†) indicate that the majority of the compounds synthesised show two excitation peaks resulting in one emission peak. As first indicated by a paper focused on similar compounds15 this probably arises from a π–π* and a n–π* electronic transition.

Conclusions Fig. 1 Crystal structure of 6d projected onto the plane of the central We have developed a convenient, relatively low cost, one pot ring.‡ preparation of polysubstituted and 2,4,6-triaryl pyridines from readily available starting materials using the confined mode of tron density from one ring to another, which relates to the operation of the VFD. This is more versatile than using the electronic properties of the molecules, including fluorescence. continuous flow mode of the device, where the additional The dihedral angles between the peripheral phenyl rings and shear associated with the viscous drag as the liquid whirls the central pyridine ring are 7.3(1), 6.4(1), 14.8(1)° for rings 12, along the tube is insuﬃcient in further accelerating the reac- 14 and 16. tions to overcome the consequential short residence time in With the availability of these compounds, we set out to gain the VFD. The photo-physical properties displayed by these a preliminary insight into their fluorescent properties. As compounds demonstrate that they may be promising candi- shown in Table 1 and Fig. 2, the fluorescence spectra of the dates for the development of putative fluorescent probes. compounds in series 3 displayed an increase in emission wave- The green chemistry metrics of the syntheses relative to length in the order 3a < 3b < 3e. The fluorescence intensity earlier studies include: (i) eﬃcient energy usage, as a constant in series 3 followed the order 3b < 3d < 3c < 3a < 3e in aceto- safe and ‘soft’ form of energy,24 in contrast to mechanoenergy nitrile, but compounds 3b, 3c and 3a were quenched signifi- used in driving solventless reactions and high energy micro- cantly in DMSO. This data strongly suggests that strong wave processing,15 (ii) establishing a one pot reaction of the electron donating groups in the parent aldehyde are a key tri-substituted pyridines in PEG which is a benign reaction factor to increasing the fluorescence intensity in this class of medium,16 in avoiding the use of toxic volatile solvents, (iii) compounds. For the 2,4,6-triarylpyridine derivatives 6a–e the avoiding the use of concentrated basic solutions as an fluorescence intensity decreases in the order 6d > 6c > 6e > 6a inherently safer process, (iv) circumventing the formation of Published on 09 June 2014. Downloaded by University of Western Australia 19/06/2014 10:47:29.

Fig. 2 (a) Fluorescence spectra for 3a–e in acetonitrile. (b) Fluorescence spectra for 3a–e in DMSO. (c) Fluorescence spectra for 6a–e in acetonitrile. (d) Fluorescence spectra for 6a–e in DMSO.

This journal is © The Royal Society of Chemistry 2014 Green Chem. View Article Online

Communication Green Chemistry

intermediate chalcone en route to the 1,5-diketone for conver- 12 G. W. V. Cave and C. L. Raston, J. Chem. Soc., Perkin Trans. sion to the corresponding pyridine, and competing formation 1, 2001, 3258–3264. of cyclohexyl ring systems,16 in minimising the generation of 13 S. Tu, T. Li, F. Shi, Q. Wang, J. Zhang, J. Xu, X. Zhu, waste, and (v) the thin film ensures that there is rapid heat dis- X. Zhang, S. Zhu and D. Shi, Synthesis, 2005, 3045–3050. sipation for highly exothermic and otherwise waste generating 14 S. Tu, R. Jia, B. Jiang, J. Zhang, Y. Zhang, C. Yao and S. Ji, reactions which have been noted in the formation of such Tetrahedron, 2007, 63, 381–388. pyridines.17 Moreover, the present findings further highlight 15 G. Yin, Q. Liu, J. Ma and N. She, Green Chem., 2012, 14, the application of the VFD, with the ability to scale up under 1796–1798. continuous flow, or scale down in confined mode, yet with 16 N. M. Smith, C. L. Raston, C. B. Smith and A. N. Sobolev, dynamic thin films present for controlling reactions beyond Green Chem., 2007, 9, 1185–1190. conventional batch processing. 17 C. B. Smith, C. L. Raston and A. N. Sobolev, Green Chem., 2005, 7, 650–654. 18 M. Adib, H. Tahermansouri, S. A. Koloogani, B. Mohammadi Acknowledgements andH.R.Bijanzadeh,Tetrahedron Lett., 2006, 47, 5957–5960. 19 M. M. Heravi, K. Bakhtiari, Z. Daroogheha and We gratefully acknowledge the Australian Research Council, F. F. Bamoharram, Catal. Commun., 2007, 8, 1991–1994. the Government of South Australia, and the Centre for 20 P. V. Shinde, V. B. Labade, J. B. Gujar, B. B. Shingate and Microscopy, Characterisation and Analysis at the University of M. S. Shingare, Tetrahedron Lett., 2012, 53, 1523–1527. Western Australia for support of this work. 21 A. Davoodnia, M. Bakavoli, R. Moloudi, N. Tavakoli-Hoseini and M. Khashi, Monatsh. Chem., 2010, 141, 867–870. 22 Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang and Notes and references Z.-H. Guan, Org. Lett., 2011, 13, 5394–5397. 23 A. Stankiewicz and J. Moulin, Chem. Eng. Prog., 2000, 22–34. ‡ Crystallographic data (excluding structure factors) for the structure in this 24 L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston, Sci. paper have been deposited with the Cambridge Crystallographic Data Centre as 3 supplementary publication no. CCDC 972818. Rep., 2013, , 2282. 25 X. Chen, J. F. Dobson and C. L. Raston, Chem. Commun., 1 S. Coe, W.-K. Woo, M. Bawendi and V. Bulovic, Nature, 2012, 48, 3703–3705. 2002, 420, 800–803. 26 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and 2 J.-D. Cheon, T. Mutai and K. Araki, Tetrahedron Lett., 2006, C. L. Raston, Green Chem., 2013, 15, 650–655. 47, 5079–5082. 27 F. M. Yasin, R. A. Boulos, B. Y. Hong, A. Cornejo, K. S. Iyer, 3 T. Y. Ohulchanskyy, M. K. Gannon, M. Ye, A. Skripchenko, L. Gao, H. T. Chua and C. L. Raston, Chem. Commun., 2012, S. J. Wagner, P. N. Prasad and M. R. Detty, J. Phys. Chem. B, 48, 10102–10104. 2007, 111, 9686–9692. 28 X. Chen, F. M. Yasin, P. K. Eggers, R. A. Boulos, X. Duan, 4 K. A. Leonard, J. P. Hall, M. I. Nelen, S. R. Davies, R. N. Lamb, K. S. Iyer and C. L. Raston, RSC Adv., 2013, 3, S. O. Gollnick, S. Camacho, A. R. Oseroﬀ, S. L. Gibson, 3213–3217. Published on 09 June 2014. Downloaded by University of Western Australia 19/06/2014 10:47:29. R. Hilf and M. R. Detty, J. Med. Chem., 2000, 43, 4488–4498. 29 A. D. Martin, R. A. Boulos, L. J. Hubble, K. J. Hartlieb and 5 D. Barton and D. Ollis, Comprehensive Organic Chemistry, C. L. Raston, Chem. Commun., 2011, 47, 7353–7355. Pergamon Press, New York, 1979, p. 4. 30 C. L. Tong, R. A. Boulos, C. Yu, K. S. Iyer and C. L. Raston, 6 A. R. Katritzky and C. M. Marson, Angew. Chem., Int. Ed. RSC Adv., 2013, 3, 18767–18770. Engl., 1984, 23, 420–429. 31 E. Eroglu, N. J. D’Alonzo, S. M. Smith and C. L. Raston, 7 G. D. Henry, Tetrahedron, 2004, 60, 6043–6061. Nanoscale, 2013, 5, 2627–2631. 8 M. D. Hill, Chem. – Eur. J., 2010, 16, 12052–12062. 32 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and 9 E. C. Constable, R. Martinez-Manez, A. M. W. C. Thompson C. L. Raston, RSC Adv., 2013, 3, 8180–8183. and J. V. Walker, J. Chem. Soc., Dalton Trans., 1994, 1585– 33 L. Yasmin, K. A. Stubbs and C. L. Raston, Tetrahedron Lett., 1594. 2014, 55, 2246–2248. 10 F. Kröhnke, Synthesis, 1976, 1–24. 34 L. Yasmin, T. Coyle, K. A. Stubbs and C. L. Raston, Chem. 11 F. Kröhnke, W. Zecher, J. Curtze, D. Drechsler, K. Pfleghar, Commun., 2013, 49, 10932–10934. K. E. Schnalke and W. Weis, Angew. Chem., Int. Ed. Engl., 35 N. M. Smith, B. Corry, I. K. Swaminathan, M. Norret and 1962, 1, 626–632. C. L. Raston, Lab Chip, 2009, 9, 2021–2025.

Green Chem. This journal is © The Royal Society of Chemistry 2014 Chapter 3 Series of papers 3.3 Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films

59 ChemComm

View Article Online COMMUNICATION View Journal | View Issue

Stereospecific synthesis of resorcin[4]arenes and

Cite this: Chem. Commun., 2013, pyrogallol[4]arenes in dynamic thin films† 49, 10932 Lyzu Yasmin,a Travis Coyle,a Keith A. Stubbsa and Colin L. Raston*b Received 10th July 2013, Accepted 9th October 2013

DOI: 10.1039/c3cc45176c

www.rsc.org/chemcomm

Acid catalysed condensation of resorcinol and pyrogallol with aromatic the crown (C4v) conformers. In these specific cases, the kinetically aldehydes using a microfluidic vortex fluidic device (VFD) under favouredchairisomerisconverted into the thermodynamically continuous flow conditions results in the selective formation of more stable crown isomer after longer reaction times. resorcin[4]arenes and pyrogallol[4]arenes as predominantly their Herein we report the synthesis of resorcin[4]arenes and

C4v isomers. Notably C2v isomers and C2h isomers can be also pyrogallol[4]arenes involving diﬀerent aldehydes using a micro-

prepared with the latter being converted to the C4v isomer when fluidic vortex fluidic device (VFD), in controlling chemical reactivity the VFD operates in confined mode. and selectivity, as part of a program on developing more eﬃcient and alternative synthetic protocols for targeted organic reactions. This Resorcin[4]arene and pyrogallol[4]arene macrocycles are a versatile system has already demonstated capability in organic reactions,17 sub-class of calixarenes with 8 or 12 upper rim hydroxyl groups, fabricating nanoparticles,18,19 exfoliating graphene,20 and wrapping respectively. These versatile molecules can be used for further graphene, graphene oxide and polymers ladden with super- chemical elaboration, for H-bonding and for metal ion complexation paramagnetic magnetite nanoparticles, around algal cells.21–23 in building complex materials. These materials include the The design of the VFD is simple with variation in the rotational formation of hexameric or dimeric capsules,1–3 tubular arrays,4 speed, angle of inclination and feed flow rates eﬀective at fine tuning and organic nanotubes.5 The traditional synthesis of these the outcome of the reaction being conducted.17 The device is macrocycles involves acid-catalyzed condensation of resorcinol designed to have jet feeds which direct liquid to the end of a tube or pyrogallol with aromatic or aliphatic aldehydes in an alcoholic and with the intense micromixing in the resulting dynamic thin

Published on 09 October 2013. Downloaded by University of Western Australia 16/05/2014 06:50:45. medium under reflux. The reaction times for these reactions vary film, the residence time can be controlled by varying both the feed from hours to several days,6–8 nature of the aldehydes also rate and the length of the tube. The thin liquid film created inside affecting reaction conditions.9–14 the rotating tube produces a very high heat and mass transfer rate.24 Resorcin[4]arene and pyrogallol[4]arenes macrocycles are It also has a longer residence time than the related spinning disc non-planar and can exist in diﬀerent forms,6,7 which include processing apparatus (SDP)24 which allows the organic reaction

the crown (C4v)boat(C2v), chair (C2h), diamond (Cs)andsaddle to occur eﬃciently in a single pass within a few minutes. The

(D2d) arrangements. The relative positions of the substituents eﬀectiveness of the VFD in controlling chemical reactivity in the at the methylene bridges can be all cis (rccc), cis–trans–cis (rctc), continuous flow mode17 is explored in the present work for 15 cis–cis–trans (rcct)andcis–trans–trans (rctt). The C4v symmetry the synthesis of the resorcin[4]arene and pyrogallol[4]arene

has the rccc configuration and simple torsion of this gives C2v macrocycles, with optimisation dependent on the choice of symmetry. The chair (C2h)isomerhasrctt configuration. Critically, the extended operating parameters relative to traditional batch the reaction conditions and the nature of the side chains at the processing, which include flow rates, rotational speeds and bridging carbon atoms affect the stereoselectivity of the cycliza- inclination angles. tion. Hoegberg16 described the condensation of various benz- The general procedure for using the VFD in continuous flow aldehydes with resorcinol and found that only two different mode for the preparation of calix[4]arenes 4a–i involved treating

stereoisomeric octols were formed, namely, the chair (C2h) and resorcinol 1 or pyrogallol 2 and aldehydes 3a–e in a 20 : 1 mixture of ethanol and concentrated hydrochloric acid (Scheme 1). This is in a School of Chemistry and Biochemistry, The University of Western Australia, contrast to earlier studies using traditional batch processing which Crawley, WA 6009, Australia typically involve a 4 : 1 ratio of solvents.7 The acidic ethanol solution b School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, 5042, Australia. E-mail: [email protected] was delivered through one feed jet to a 10 mm diameter standard 1 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ NMR tube at a flow rate of 1 mL min . The rotational speed, angle c3cc45176c of inclination of the tube and temperature were set at 7000 rpm,

10932 Chem. Commun., 2013, 49, 10932--10934 This journal is c The Royal Society of Chemistry 2013 View Article Online Communication ChemComm

C4v and C2h being 3 : 4. Possible reasons for the formation of this mixture lie in the substitution pattern of vanillin which may cause steric hindrance during the cyclization and so the

amount of the C4v isomer may therefore increase. Interestingly, the VFD significantly reduces the reaction time for the preparation of 4h, which is consistent with the microfluidic platform providing a ‘soft’ form of energy to increase molecular collisions 17 for reactions under diﬀusion control. As a comparison the C2h isomer is usually prepared in 5 days using traditional method 10 processing with no formation of the C4v isomer. We further investigated whether the percentage conversion of the stereoisomers found using vanillin and resorcinol 1 could be controlled by changing the diﬀerent reaction parameters for the Scheme 1 General reaction procedure for the preparation of calix[4]arenas. (a) Ethanol, conc. HCl, 80 1C, 7000 rpm, 451 inclination angle, 1 mL min1. VFD. Systematic variation of rotational speed, temperature, flow rate, angle of tilt and acid used, resulted in formation of both the

C4v and C2h stereoisomers in all cases, albeit with diﬀerent percent 451 and 80 1C respectively, with the choices of speed and angle conversions and diﬀerent ratios of the isomers (Table 2). The based on earlier work using this instrument.17 In most cases rotational speed is a key processing parameter of the VFD, in the reaction produced a precipitate, which was collected using controlling the thickness of the dynamic thin film.24 simple filtration. The solid products were washed with water to At high speed (7000 rpm) the conversion to 4h was high

remove any acid and purified, by crystallisation from ethanol, yielding with a mixture of the C4v and C2h isomers whereas at to give the desired compounds 4a–i in good yields (Table 1). All lower speed (3000 rpm) the ratio was more in favour of the C2h compounds obtained had 1H and 13C NMR spectra that were isomer. The angle of tilt of the VFD was also seen to play an consistent with literature values6,7,10,13 previously reported for important role in the reactions. At an angle of 451, where both

C4v isomers (see ESI†). Of note is that in all cases the reactions gravitational and centrifugal forces create shear within the were conducted using a single pass on the VFD which translates resulting thin film formed, a higher conversion to C4v was to 10 min processing for 10 mL of solution, at the designated observed compared to an angle of 01 where only centrifugal flow rate of 1 mL min1. forces are present.17 The macrocycles 4a–f were characterised as their rccc crown The eﬀect of flow rate was also investigated by varying the input 1 1 (C4v) isomer, which is the favoured isomer formed using traditional rate from 1 mL min to 3 mL min , over 1 mL increments. We batch processing for aliphatic aldehydes with resorcinol 1 and found that the best rate for the conversion to 4h of C4v isomers pyrogallol 2. There were no signs of the formation of the other was 1 mL min1 (43%), with higher flow rates resulting in lower

isomers, in particular the kinetically favoured rctt chair (C2h). Of conversions. This could be attributed to the reduced residence note was the preparation of the resorcin[4]arene 4g which was time of the liquid in the VFD and therefore less chance for isolated exclusively as the rccc crown isomer. Previous traditional conversion. The optimal temperature was found to be 80 1C and 7 Published on 09 October 2013. Downloaded by University of Western Australia 16/05/2014 06:50:45. literature preparations of 4g were found to only form the rctt switching the acid used from hydrochloric acid to p-toluene

chairisomer(C2h) after short reaction times and only after longer sulfonic acid or acetic acid in ethanol resulted in reduced reaction times did the formation of the rccc crown isomer result. conversion and no conversion, respectively. Of interest was that the reaction of pyrogallol 2 with vanillin The VFD is unique in that it has two formats under which

afforded exclusively the pyrogallol[4]arene macrocycle 4i as its C2v chemical reactions can take place, continuous flow and confined (boat) isomer in high yield. mode.17 To evaluate the eﬀects of performing chemical reactions The calix[4]arene macrocycle 4h (synthesised from vanillin in the confined mode we took the mixture of isomers of 4h

and resorcinol 1) was prepared in both the rccc C4v and rctt C2h isomers under VFD continuous flow conditions with the ratio of Table 2 Investigation into the conformation of 4husing diﬀerent parameters of reaction in VFD under continuous flow conditions

Table 1 Synthesis of calixarene macrocycles using continuous flow VFD operating Variation of C4v C2h Yield at 7000 rpm, 451 tilt angle and 80 1C at a flow rate of 1 mL min1 Parameters parameters (%) (%) (%)

Product –R0 –R Yield (%) Isomer Rotational speed (rpm) 7000 43 57 99 3000 30 70 96 4a 3a H32 C4v Angle of inclination (degrees) 45 43 57 99 4b 3b H43 C4v 0277381 1 4c 3c H40 C4v Flow rate (mL min ) 1 43 57 99 4d 3a OH 42 C4v 3257574 4e 3b OH 42 C4v Temperature (1C) 80 43 57 99 4f 3c OH 75 C4v 60 14 86 37 4g 3d H56 C4v Acid HCl 43 57 99 4h 3e H99 C4v and C2h p-TSA 37 63 90 4i 3e OH 84 C2v Acetic acid 0 0 0

This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 10932--10934 10933 View Article Online ChemComm Communication

times did not improve this conversion. This also provides further evidence that intense shear is present under confined mode operation of the VFD, and arises from the cross vector of centrifugal force and gravity.20 Of interest is that compound 4i

in the C2v isomer cannot be converted to the C4v isomer using the same approach. In conclusion, we have established a novel and facile method for the synthesis of diﬀerent resorcin[4]arenes and pyrogallol[4]arenes

as the C4v isomer, with one exception, using the microfluidic VFD under continuous flow conditions. The type of isomers that can be formed, as well as conversion between them, can be controlled by varying the parameters of the VFD, with an added advantage of significantly reducing the reaction times and the amount of catalyst required. This method has potential for controlling for formation of other calixarenes, and a plethora of chemical reactions. Support of this work by the Australian Research Council, The University of Western Australia and Centre for Microscopy, Characterisation and Analysis at the University of Western

Scheme 2 VFD conditions: confined mode, ethanol, conc. HCl, 60 1C, 7000 rpm, Australia is greatly acknowledged.

451 inclination angle, 1 mL solution of 4h (1 mmol, C4v and C2h) treated for one hour. Notes and references

1 L. R. MacGillivray and J. L. Atwood, J. Solid State Chem., 2000, 152, 199. 2 J. L. Atwood, L. J. Barbour and A. Jerga, Chem. Commun., 2001, 2376. 3 G. W. V. Cave, J. Antesberger, L. J. Barbour, R. M. McKinlay and J. L. Atwood, Angew. Chem., Int. Ed., 2004, 43, 5263. 4 G. W. Orr, L. J. Barbour and J. L. Arwood, Science, 1999, 285, 1049. 5 S. J. Dalgarno, G. W. V. Cave and J. L. Atwood, Angew. Chem., Int. Ed., 2006, 45, 570. 6 A. G. S. Hoegberg, J. Org. Chem., 1980, 45, 4498. 7 L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant, J. C. Sherman, R. C. Helgeson, C. B. Knobler and D. J. Cram, J. Org. Chem., 1989, 54, 1305. 8 J. B. Niederl and H. J. Vogel, J. Am. Chem. Soc., 1940, 62, 2512. 9 R. J. M. Egberink, P. L. H. M. Cobben, W. Verboom, S. Harkema and D. N. Reinhoudt, J. Inclusion Phenom. Mol. Recognit. Chem., 1992, 12, 151. 10 K. N. Rose, M. J. Hardie, J. L. Atwood and C. L. Raston, J. Supramol. Chem., 2001, 1, 35. 1 Published on 09 October 2013. Downloaded by University of Western Australia 16/05/2014 06:50:45. Fig. 1 Part of the 400 MHz H NMR spectrum of (a) compound 4h (3 : 4 mixture 11 B. A. Roberts, G. W. V. Cave, C. L. Raston and J. L. Scott, Green of C4v and C2h isomers), (b) intermediate product 4h (30 min) and (c) compound Chem., 2001, 3, 280. 4h (predominating C4v isomer). * corresponds to the C4v isomer and corre- 12 M. Hedidi, S. M. Hamdi, T. Mazari, B. Boutemeur, C. Rabia,

sponds to the C2h isomer. F. Chemat and M. Hamdi, Tetrahedron, 2006, 62, 5652. 13 M. Funck, D. P. Guest and G. W. V. Cave, Tetrahedron Lett., 2010, 51, 6399. 14 C. Yan, W. Chen, J. Chen, T. Jiang and Y. Yao, Tetrahedron, 2007, (C4v and C2h) and treated them in the VFD in an acidic medium 63, 9614. at 60 1C for one hour (Scheme 2). After this time and isolation 15 V. K. Jain and P. H. Kanaiya, Russ. Chem. Rev., 2011, 80, 75. of the material we found that the ratio of the two isomers had 16 A. G. S. Hoegberg, J. Am. Chem. Soc., 1980, 102, 6046. 17 L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston, Sci. Rep., 2013, changed to a point that the C4v isomer was almost exclusively 3, 2282. present, with this conversion being confirmed by 1H NMR 18 F. M. Yasin, R. A. Boulos, B. Y. Hong, A. Cornejo, K. S. Iyer, L. Gao, spectroscopy (Fig. 1). We rationalise that in the original H. T. Chua and C. L. Raston, Chem. Commun., 2012, 48, 10102. 19 X. Chen, F. M. Yasin, P. K. Eggers, R. A. Boulos, X. Duan, R. N. Lamb, continuous flow mode reaction conditions, the reaction time K. S. Iyer and C. L. Raston, RSC Adv., 2013, 3, 3213. (residence time) is insuﬃcient for conversion of the lower 20 X. Chen, J. F. Dobson and C. L. Raston, Chem. Commun., 2012, symmetry C isomer to the thermodynamically more stable 48, 3703. 2h 21 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and C. L. Raston, C4v isomer. Only after treatment in the confined mode in the Green Chem., 2013, 15, 650. VFD was this conversion able to proceed. Notably when the 22 E. Eroglu, N. J. D’Alonzo, S. M. Smith and C. L. Raston, Nanoscale, same mixture was treated using the same reaction conditions 2013, 5, 2627. 23 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and C. L. Raston, as in batch mode, there was only 46% conversion of the C2h RSC Adv., 2013, 3, 8180. isomer to the C4v isomer after one hour, and extended reaction 24 K. S. Iyer, C. L. Raston and M. Saunders, Lab Chip, 2007, 7, 1800.

10934 Chem. Commun., 2013, 49, 10932--10934 This journal is c The Royal Society of Chemistry 2013 Chapter 3 Series of papers 3.4 Vortex fluidic promoted Diels-Alder reactions in aqueous medium

63 Tetrahedron Letters 55 (2014) 2246–2248

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier.com/locate/tetlet

Vortex ﬂuidic promoted Diels–Alder reactions in an aqueous medium ⇑ Lyzu Yasmin a, Keith A. Stubbs a, Colin L. Raston b, a School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia b School of Chemistry and Physical Sciences, Flinders University, Bedford Park, SA 5042, Australia article info abstract

Article history: ‘Soft energy’ provided within a thin film microfluidic platform, namely a vortex fluidic device (VFD), is Received 6 January 2014 effective in accelerating and promoting Diels–Alder reactions in the absence of any catalyst. Diels–Alder Revised 30 January 2014 cycloadducts generated from different 9-substituted anthracenes and N-maleimides are formed in high Accepted 20 February 2014 yield in an aqueous medium using the confined mode of operation of the VFD. Available online 3 March 2014 Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Diels–Alder cycloaddition 9-Substituted anthracenes N-maleimides Thin film microfluidics Vortex fluidics

The loss of aromatic stabilization energy is the main cause for promoted the reaction at the terminal 1,4-position rather than the much slower Diels–Alder cycloaddition reactions involving the central 9,10-position of the anthracene ring.15 Moreover, they aromatic molecules relative to reactions involving aliphatic com- found another similar bowl-shaped host attaining efficient cata- pounds.1 Anthracene is a versatile unit in building structural diver- lytic turnover in coupling the same substrates with the conven- sity and a plethora of reactions exist for modifying and tional regiochemistry. In the present contribution we have functionalizing its ring systems.2 An example of this diversity is developed the use of a thin film microfluidic platform, namely a the ability for anthracene to act as a highly conjugated diene in vortex fluidic device (VFD) in providing constant ‘soft energy’ for the Diels–Alder reaction for a diverse range of dienophiles, adding promoting Diels–Alder reactions of anthracenes substituted at across the 9 and 10 positions.3 the 9,10-positions in high molar ratio aqueous media. Several strategies have been developed to promote Diels–Alder We recently developed the VFD as a thin film microfluidic de- reactions of inert aromatic compounds. In general, approaches vice with high Reynolds numbers. This contrasts with conventional used to overcome the resonance energy of the starting material microfluidic devices involving moving of liquids through channels, in Diels–Alder reactions can be divided into two categories: (i) which have low Reynolds numbers.16 The VFD is an attractive where there is relief of strain in distorted aromatic cores which alternative because it has dynamic thin films where there is in- compensates for the loss in aromaticity,4,5 and (ii) the use of harsh tense shear, with high mass and heat transfer,17 in contrast to tra- conditions such as high temperatures and pressures, or the use of ditional batch processing. VFD processing has proven capability in strong Lewis acids that can enhance orbital interactions.6–9 Cataly- exfoliating graphene from graphite,18 disassembling molecular sis of Diels–Alder reactions through formation of supramolecular capsules of p-phosphonic acid calix[5]arene,19 controlling the assemblies is becoming increasingly popular. Large molecules con- growth of palladium nano-particles on carbon-nano-onions20 taining a cavity (e.g., cyclodextrins10 or related basket11 or capsule- forming graphene-algae hybrid materials,21,22 controlling the pore like12 structures) can bind both Diels–Alder reagents simulta- size and wall thickness of mesoporous silica at ambient tempera- neously and promote their reaction. The same principle accounts ture,23 and controlling the polymorphs of calcium carbonate.24 for catalysis by antibodies13 and enzymes.14 We have also reported the use of the VFD in controlling reactivity Fujita et al. reported that using an aqueous organopalladium and selectivity in organic synthesis for a series of triarylpyridines25 cage, unusual regioselectivity was observed in the Diels–Alder cou- and calix[4]arenes.26 pling of anthracene and maleimide guests. Intriguingly, this cage The VFD can operate under a confined mode or a continuous flow mode, depending on the nature and reactivity of the starting ⇑ materials. The continuous flow mode has relatively short residence Corresponding author. Tel.: +61 8 8201 7957; fax: +61 8 8201 2905. times which can be an issue for some organic reactions, and E-mail address: colin.raston@flinders.edu.au (C.L. Raston). http://dx.doi.org/10.1016/j.tetlet.2014.02.077 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. L. Yasmin et al. / Tetrahedron Letters 55 (2014) 2246–2248 2247 contrast with the confined mode which is not residence time dependent. In the confined mode of VFD processing, as the 10 mm diameter tube containing a finite volume of liquid rotates, a dynamic thin fluid film forms on the wall of the tube where there is intense shear, at least for tilt angles h >0°. The average thickness of the fluid film depends on the processing parameters, including rotational speed, h and the volume of the liquid.25 The present work focuses on using the confined mode of operation of the VFD to promote Diels–Alder reactions involving anthracenes and maleimides, establishing the ability to effect the reactions in media Scheme 1. Diels–Alder reaction for optimizing the VFD operating parameters. with a high mole fraction of water, without the need for catalysts, and with relatively short reaction times. Initially, our efforts were directed at the typical cycloaddition Table 1 reaction between 9-hydroxymethylanthracene (1a) and N-phenyl- Reaction conditions for preparing cycloadduct 3a maleimide (2a) in water. For reasons of cost, safety, and environ- Entry Temp Time Solvent Reaction Conversion mental concerns, water is a desirable solvent for chemical (°C) (min) modea (%) reactions, and the study of organic reactions in aqueous solvent 27 19060H2O VFD 0 has an intriguing history. The pioneering work of Breslow et al. b 25010H2O/EtOH VFD 67 established that Diels–Alder reactions proceed faster (as high as b 35020H2O/EtOH VFD 78 b 700-fold) and have a higher endo/exo selectivity in water than in 45030H2O/EtOH VFD 91 10 b organic solvents. The small size and high polarity of water mole- 56010H2O/EtOH VFD 70 b cules, as well as the three-dimensional hydrogen bonded network 65030H2O/EtOH Batch 15 system of bulk water, provide some unique properties which in- a VFD is in the confined mode, at 45° tilt angle, and 7000 rpm. clude a large cohesive energy density, high surface tension, and a b 10% ethanol in water. hydrophobic effect.28 These unique properties are believed to be responsible for the rate and selectivity enhancements of Diels–Al- resulted in almost 67% conversion into the cycloadduct 3a (deter- der reactions. The main difficulty of the above reaction was the low mined by 1H NMR spectroscopy). The reaction time was then in- solubility of the anthracene in water, which was addressed by the creased from 10 min to 30 min (entries 3 and 4) and the percent addition of a suitable alcohol as a co-solvent, ca. 10%. The effect of conversion into product gradually increased up to 91%. When the addition of different alcohols has been studied extensively by Blok- reaction temperature was increased from 50 °Cto60°C for zijl et al.29,30 They reported that a number of Diels–Alder reactions 10 min, we observed only a slight increase in conversion 70% to show an increase in rate upon addition of small amounts (a few 3a (entry 5). As a control, we conducted the best replicated reac- mol %) of suitable alcohols. This trend has been explained by tion conditions (entry 4) in a batch mode process and interestingly, assuming an enhancement of hydrophobic interactions in such only a very low conversion was observed (entry 6). It is noteworthy media. The alcohol molecules are expected to promote the water that in every case we produced only the central 9,10-cycloadduct, structure, which in turn favors the entropic contribution of hydro- with no evidence for any terminal 1,4-cycloadduct. phobic interactions.31 Breslow et al. also studied the reaction be- Inside the reaction tube of the VFD both centrifugal and gravi- tween substituted 9-hydroxymethyl-anthracene and maleimides tational forces are active at the 45° tilt angle. According to fluid in alcohol–water mixtures, establishing that a small amount of dynamics, Stewartson/Ekman layers are formed in the thin films an alcohol co-solvent does not interfere with the ability of water created at this angle.18 The intense shear layers in dynamic thin to solvate ionic transition states (activated complexes), but that film accelerate the Diels–Alder reaction which results in higher the co-solvent is recruited to help solvate the hydrophobic por- yields of 3a. The choice of rotating speed of the VFD is also impor- tions. The induced solubility perturbations reflect the solvation of tant for promoting this reaction. In previous studies,25 we reported the reactants by the co-solvent. Overall, they successfully corre- that a higher speed favors the progress of organic reactions, but lated the rate constant with the solubility of the starting materials interestingly, here we found changing the speed had little effect for each Diels–Alder reaction. From these relations the change in on the reaction outcome (Fig. 1). Indeed for a tilt angle of 45° the solvent accessible surfaces between initial state and activated yield increases as speed increases, to almost quantitative conver- complex was estimated.31 Fujita et al.15 described the same reac- sion at 5000 rpm, with then a slight reduction for even higher tion of 1a and 2a using a self-assembled coordination cage which speeds. This discontinuity is becoming evident for a number of decreased the entropic cost of the reaction. Unfortunately, using applications of the VFD, including a discontinuity for the simple either a batch or control experiment at 90 °C for 5 h in water, re- dimerization of cyclopentadiene, although this is in the absence sulted in incomplete reaction with only trace amounts of product of any solvent.25 Clearly this is a special phenomenon which war- formed.15 rants a detailed understanding of the fluid dynamics and will fea- Use of the VFD to prepare 3a from the starting materials 1a and ture in a separate study. 2a was investigated (Scheme 1). A 10 mm diameter glass tube with After establishing the optimized results for 9-hydroxymethyl- a cap was used to carry out the reaction in the confined mode. The anthracene and N-phenylmaleimide, the scope of the Diels–Alder reaction parameters of speed and tilt angle for VFD were fixed at reactions for different 9-substituted anthracenes and different N- 7000 rpm and 45°, respectively, which were optimized processing substituted maleimides was investigated (Scheme 2 and Table 2). parameters for previous studies on the use of the VFD in organic Overall the results showed that there was high conversion into reactions.25 Experimentally, the substrates 1a and 2a were mixed the expected 9,10-cycloadducts 3b-i, except for 9-carboxylic acid together in water or water with a small mole fraction of ethanol, anthracene 3j. It may be the presence of the electron-withdrawing and the temperature and reaction time were varied to optimize carboxylic acid moiety on the anthracene ring that inhibits this the conversion. We first took both reactants 1a and 2a in water reaction. in the VFD at 50 °C for 1 h. However, this resulted in incomplete In summary, we have developed a highly efficient and more be- formation of 3a (Table 1, entry 1). On the other hand, a 9:1 nign methodology using a high mole fraction aqueous medium water/ethanol solvent system at 50 °C for 10 min (entry 2), with ethanol in a microfluidic platform for Diels–Alder reactions, 2248 L. Yasmin et al. / Tetrahedron Letters 55 (2014) 2246–2248

Acknowledgments

We gratefully acknowledge the Australian Research Council and the Centre for Microscopy, Characterisation and Analysis at the University of Western Australia for supporting this work.

Supplementary data

Supplementary data (General experimental, data and copies of 1H NMR and 13C NMR spectra of new compounds) associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.tetlet.2014.02.077.

References and notes

Figure 1. Percent conversion for the reaction in Fig. 1, using the VFD at 45° tilt 1. Horiuchi, S.; Murase, T.; Fujita, M. Chem. Asian J. 2011, 1839,6. angle, h, as the speed is varied. 2. Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078. 3. Breslow, R.; Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 1901,24. 4. Bickelhaupt, F.; de Wolf, W. H. J. Phys. Org. Chem. 1998, 11, 362. 5. Chordia, M. D.; Smith, P. L.; Meiere, S. H.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2001, 123, 10756. 6. McCabe, J. R.; Eckert, C. A. Acc. Chem. Res. 1974, 7, 251. 7. Kiselev, V. D.; Konovalov, A. I. Russ. Chem. Rev. 1989, 58, 230. 8. Chambers, R. D.; Edwards, A. R. Tetrahedron 1998, 54, 4949. 9. Asano, T.; Le, N. W. J. Chem. Rev. 1978, 78, 407. 10. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816. 11. Hirst, S. C.; Hamilton, A. D. J. Am. Chem. Soc. 1991, 113, 382. 12. Kang, J.; Santamaría, J.; Hilmersson, G.; Rebek, J. J. Am. Chem. Soc. 1998, 120, 7389. 13. Gouverneur, V.; Houk, K.; de Pascual-Teresa, B.; Beno, B.; Janda, K.; Lerner, R. Science 1993, 262, 204. 14. Siegel, J. B.; Zanghellini, A.; Lovick, H. M.; Kiss, G.; Lambert, A. R.; St.Clair, J. L; Scheme 2. General scheme for the reactions in Table 2. Gallaher, J. L; Hilvert, D.; Gelb, M. H; Stoddard, B. L; Houk, K. N; Michael, F. E; Baker, D. Science 2010, 329, 309. 15. Yoshizawa, M.; Tamura, M.; Fujita, M. Science 2006, 312, 251. 16. Thorsen, T.; Roberts, R. W.; Arnold, F. H.; Quake, S. R. Phys. Rev. Lett. 2001, 86, Table 2 4163. Synthesis of compounds 3 under VFD at 50 °C, 5000 rpm, and 45° tilt angle for 30 min 17. Iyer, K. S.; Raston, C. L.; Saunders, M. Lab Chip 2007, 1800,7. 18. Chen, X.; Dobson, J. F.; Raston, C. L. Chem. Commun. 2012, 48, 3703. Entry R1 R2 Product Conversion (%) 19. Martin, A. D.; Boulos, R. A.; Hubble, L. J.; Hartlieb, K. J.; Raston, C. L. Chem.

1 –CH2OH Ph 3a 99 Commun. 2011, 47, 7353.

2 –CH3 Ph 3b 99 20. Yasin, F. M.; Boulos, R. A.; Hong, B. Y.; Cornejo, A.; Iyer, K. S.; Gao, L.; Chua, H. T.; Raston, C. L. Chem. Commun. 2012, 48, 10102. 3 –CH2OH Cyclohexyl 3c 91 21. Wahid, M. H.; Eroglu, E.; Chen, X.; Smith, S. M.; Raston, C. L. Green Chem. 2013, 4 –CH3 Cyclohexyl 3d 93 15, 650. 5 –CH OH Bn 3e 95 2 22. Wahid, M. H.; Eroglu, E.; Chen, X.; Smith, S. M.; Raston, C. L. RSC Adv. 2013, 3, 6 –CH Bn 3f 98 3 8180. 7 –CH OH n-Pr 3g 97 2 23. Tong, C. L.; Boulos, R. A.; Yu, C.; Iyer, K. S.; Raston, C. L. RSC Adv. 2013, 3, 18767. 8 –CH3 n-Pr 3h 99 24. Boulos, R. A.; Harnagea, C.; Duan, X.; Lamb, R. N.; Rosei, F.; Raston, C. L. RSC Adv. 9 –CHO Ph 3i 53 2013, 3, 3284. 10 –CO2HPh 3j 0 25. Yasmin, L.; Chen, X.; Stubbs, K. A.; Raston, C. L. Sci. Rep. 2013, 3, 2282. 26. Yasmin, L.; Coyle, T.; Stubbs, K. A.; Raston, C. L. Chem. Commun. 2013, 49, 10932. 27. Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35,68. with signiﬁcantly reduced processing times. We believe this meth- 28. Breslow, R. Acc. Chem. Res. 1991, 24, 159. 29. Blokzijl, W.; Blandamer, M. J.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1991, 113, od has the ability to play an integral role in the chemical synthesis 4241. sector from an environmental, quality, safety, and economical 30. Blokzijl, W.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1992, 114, 5440. perspective. 31. Breslow, R.; Zhu, Z. J. Am. Chem. Soc. 1995, 117, 9923. Chapter 4 Conclusions and Future work 4. Conclusions and future work

An alternative strategy in minimizing the generation of by-products and waste is PI strategies which lie beyond the use of solventless and microwave processing, as in dynamic thins films, which can allow gaining control of formation of the kinetic favoured product over the thermodynamic favoured product. A green, facile and scalable synthetic method was established to synthesise different types of organic compounds using the VFD as a form of PI. The VFD was found to be an attractive and feasible technology for organic synthesis because of its distinctive characteristics and its capability of being tailored to a wide range of important applications. The optimization of this device was done by the dimerization of CpH and MeCpH as model reactions and the following was concluded:

• Very fast organic reactions are completed more effectively in VFD than in a normal batch stirred vessel. The VFD can control the residence time for any chemical reaction by using the continuous and confined mode of operation. It can also control the chemical reactivity and selectivity of the organic compounds produced by changing these modes of operation. Confined mode of operation is for a fixed volume of liquid which overcomes the need for using large volumes of liquids for shearing processes associated with conventional continuous film flow microfluidic platforms. • The VFD has different shear regimes in the thin films, depends on the tilt angle θ, of the rapidly rotating tube, which was greatest at 45° and 90°. This angle defines different shear regimes corresponding to different orientations of the centrifugal force relative to gravity, for which the fluid dynamics is presumably complex. • Rotational speeds have been found to be an extra variable for reaction optimization, with higher speeds giving better mixing, heat/mass transfer and shorter residence times. • In continuous flow at low flow rate, the conversion increases as tilt angle θ increases which establishes the contribution from the shear associated with viscous drag. At low flow rates the film thickness is expected to be thinner than at high flow rates for the same speed, and with thicker films the overall contribution of the shear from the viscous drag will be reduced.

Chapter 4 Conclusions and Future work The above optimization of the VFD has been conducted for different organic reactions and has established the utility of using this inexpensive microfluidic device for improving the outcome of chemical reactions. However, a limitation of the VFD is the continuous flow operation for highly viscous liquids which may clog the outlet system. Other limitations of the VFD include the precipitation of product and when using solvents when the reaction is carried out at temperatures above the corresponding boiling point.

A synthetic route to access amino-functionalized 2,4,6-triarylpyridines using a dynamic thin film has been developed using the VFD where 1,5-diketones are the intermediate product. Specifically, access of intermediate 1,5-diketone of 4´-(p- dimethylaminophenyl)-2,6-bis(4-aminophenyl)pyridines has been described, overcoming a series of competing reactions and effectively controlling chemical reactivity and selectivity. This reaction is not possible or is inherently difficult using traditional batch processing because of poor heat and mass transfer. The one-pot reaction of amino functionalized 2,4,6-triarylpyridines has been established under the continuous flow conditions of the VFD in a single pass, in the presence of NH4OAc and PEG.

A method of synthesis of new fluorescent polysubstituted and triarylpyridine compounds with high functionality has been developed using the VFD which is very convenient, low cost and time saving. Polyaryl pyridine and N,N´-dimethyl containing 2,4,6-triarylpyridines were accessible in the confined mode from easily available raw materials in a one-pot reaction using NH4OAc in a moderate yield where PEG300 was used as a solvent. This is more versatile to using the confined mode than using the continuous flow mode of the device, where the additional shear associated with the viscous drag as the liquid whirls along the tube is insufficient in further accelerating the reactions to overcome the consequential short residence time in the VFD. UV-Vis and fluorescence spectra of these compounds were also investigated in different solvents. The synthetic and photophysical properties displayed by these compounds indicate that they would be promising candidates for fluorescent probes and fluorescent markers.

The green chemistry metrics of the VFD operating triarylpyridine syntheses has been significantly improved in comparison to previous studies using other methods. The green chemistry metrics of this method include the use of a ‘soft’ form of energy, avoiding the use of toxic chemicals and circumventing the formation of the intermediate

Chapter 4 Conclusions and Future work chalcone en route to the 1,5-diketone. In addition, rapid heat transfer on the thin film for highly exothermic reactions is a favoured condition for pyridine formation.92

A novel and facile method has been developed for the synthesis of different resorcin[4]arenes and pyrogallol[4]arenes from different aromatic or aliphatic alcohol and resorcinol or pyrogallol, using the VFD under continuous flow using acid-catalysis.

The thermodynamically stable C4v isomer was found as a predominant isomer but the type of isomers that can be formed and isomer conversions can be controlled by varying the parameters of the VFD, with an added advantage of significantly reduced reaction times and the amount of catalyst required. This method has prospective for controlling the formation of other calixarenes.

A highly efficient and completely green methodology has been developed using the VFD in confined mode as a microfluidic platform for aromatic Diels-Alder reactions. It has been reported that reactions in media with a high mole fraction of water with alcohol can be affected, without the need for any catalysts. The intense shear layers in dynamic thin films speed up the Diels-Alder reaction resulting in high yields. This method has the potential to perform Diels-Alder reactions using naphthalene, perylene or triphenylene, which are inert under typical reaction conditions.

With hierarchical control, the VFD is may also have application in different functional group conversions. In the future, the VFD could be used for the reactions of gases with liquids, taking benefit of the high mass transfer of gases at the dynamic interface between the two states. The VFD is modular and can be easily modified for increasing the intensity of shear or micromixing, in changing the nature of the tube, with surface texture features. The VFD can also integrate field effects, including standard light sources and lasers. It has high throughput processing capabilities for developing libraries of nanomaterials and organic compounds. Several reactions can potentially be telescoped within a single platform, or sequential platforms, with the ability to carry out reactions in an inert atmosphere using a gas feed.

In conclusion, this PhD thesis presents the results mainly focused on the optimization of the VFD and translated this optimization for different organic syntheses, for the first time. Generally, these reactions were not successful or very challenging in normal batch processing. The ability of controlling chemical reactivity and selectivity by the unique dual operating systems of this device has been reported. In addition, this low cost device significantly reduces the reaction time from days or hours to minutes making it very 69

Chapter 4 Conclusions and Future work promising for use in the chemical industry. Moreover, using the continuous flow microfluidic device, minimizing the catalysis requirement, and using PEG and water as the reaction medium incorporates green chemistry into the research.

Chapter 5 Online Support Information for Published Articles 5. Online Support Information for Published

Articles

Online supporting information for the papers presented in Chapter 3, are organized in a sequence accordingly.

5.1 Supporting information for “Optimising a vortex fluidic device for controlling chemical reactivity and selectivity”

Materials and methods

All commercially obtained chemicals were used as received unless otherwise specified. Dicyclopentadiene was obtained from Fluka. Methylcyclopentadiene- dimer was obtained from Alfa-Aesar. p-Aminoacetophenone was purchased from Fluka. N,N-Dimethylaminobenzaldehyde was obtained from BDH. 2-Napthaldehyde, 4-bromobenzaldehyde and vanillin were purchased from Alfa Aesar, Aldrich and Unilab respectively. Thin layer chromatography (TLC) was conducted with Silica gel 60 F254. Visualization was effected by ultraviolet light (254 nm). Melting points were measured by Electrothermal. 1H and 13C NMR spectra were recorded on Varian NMR spectrometer at 400 MHz and 100 MHz respectively. Percent conversion for Figure 1 and 2 was calculated using integration of characteristic signals in the 1H NMR spectrum of cyclopentadiene and methycyclopentadiene respectively. Uncertainties were calculated based on the standard deviation of the mean of three measurements.

Vortex fluidic device

A photograph showing a prototype VFD used in the study, with explanations, is provided in Fig. S1.

Chapter 5 Online Support Information for Published Articles

Figure S1. A prototype VFD showing the overall set up. The jet feed inlets are connected to a peristaltic pump, and the heating unit is modular, locking into place with two pins, with the tilt angle adjustable on a locking pivot system.

Experimental procedures

1. Dimerization of Cyclopentadiene and Methyl cyclopentadiene 1.1. Synthesis of Cyclopentadiene/Methyl cyclopentadiene from its Dimer:

Cyclopentadiene and methylcyclopentadiene were synthesised from their dimer by fractional distillation at 165°C and 180°C respectively before use. The monomers readily dimerize at room temperature, and thus the materials were always kept in a cool place.

1.2. Dimerization of cyclopentadiene by VFD at confined mode: For each experiment cyclopentadiene (0.2 mL) was taken in a 10 mm diameter and 15 cm long NMR tube with a cap unless otherwise stated. Percent conversion was obtained using 1H NMR analysis.

(a) Varying the angle: The speed and time of VFD were set at 7000 rpm and 1 hour respectively. Seven different experiments were carried out at seven different tilt angles (0, 15, 30, 45, 60, 75 and 90 degrees). (Fig.2-a)

(b) Varying the Time: The speed and tilt angle of VFD were set at 7000 rpm

Chapter 5 Online Support Information for Published Articles and 45° respectively. Four different experiments were conducted at four different time lengths (0.5, 1, 2 and 3 h). Similar experiments were carried out at a 0° tilt angle. (Fig.2-b)

(c) Varying the speed: The time and tilt angle of VFD were set at 1 hour and 45° respectively. The experiments were carried out at six different speeds, 1000, 2000, 3000, 5000, 7000 and 9000 rpm. (Fig.2-c)

1.3. Dimerization of methylcyclopentadiene by VFD at continuous flow mode:

For the continuous flow method, methylcyclopentadiene was kept in a sample vial which was cooled in an ice bath. Products were collected at steady state position of reactant inside the glass tube. Percent conversion was obtained using 1H NMR analysis.

(a) Varying flow rates at different tilt angles: The speed was fixed at 7000 rpm for all experiments at different five flow rates (0.1, 0.25, 0.5, 0.75 and 1.0 mL/min) and at different nine tilt angles (0, 15, 30, 37.5, 45, 52.5, 60, 75 and 90 degrees). (Fig.3-a)

(b) Varying speeds at different tilt angles: The flow rate was set at 0.1mL/min for all experiments at different three speeds (5000, 7000 and 9000 rpm) and at nine different tilt angles (0, 15, 30, 37.5, 45, 52.5, 60, 75 and 90 degrees). (Fig.3-b)

2. Synthesis 2.1. General route for synthesis of chalcones (3): p-Aminoacetophenone (1) (1 mmol) was added to a stirred solution of PEG 300 (1 mL) and crushed sodium hydroxide (1 mmol) in the same flask. Benzaldehyde (2) (1 mmol) was then added to a stirred solution of PEG 300 (1 mL) in another flask. Both solutions were then mixed in a capped 10 mm dimater glass tube and spun in the VFD at 7000 rpm, 45° degree tilt angle at 80°C (for 3a and 3d) or ambient temperature (for 3b and 3c) for 30 minutes in confined mode. Water (25 mL) was the added and the resulting yellow precipitate was collected by suction filtration and dried in vacuo. 73

Chapter 5 Online Support Information for Published Articles

2.2. General route for synthesis of 1,5-diones (4): p-Aminoacetophenone (1) (1 mmol) and crushed sodium hydroxide (2 mmol) were added to a stirred solution of PEG 300 (1 mL) in a flask. Benzaldehyde (2) (1 mmol) was then added to a stirred solution of PEG 300 (1 mL) in another flask. Both solutions were then passed through the VFD using continuous flow mode. The VFD conditions were 80°C, 7000 rpm, 0 degree tilt angle and a flow rate of 0.1mL/min. After cooling the reaction mixture to room temperature, water was added to aid precipitation. The yellow precipitate as mixture of 1,5- diketone (4) and chalcone (3) was collected by suction filtration and dried. The crude product was purified by column chromatography over silica gel using hexane:ethyl acetate (1:2) as eluent to obtain a pure product (5) as light brown solid.

2.3. Synthesis of 2,4,6-triarylpyridine (5) using route (iv): p-Aminoacetophenone (1) (1 mmol) was added to a stirred solution of PEG 300 (1 mL) and excess NH4OAc (400 mg) in a flask. Benzaldehyde (2) (1 mmol) was then added to a stirred solution of PEG 300 (1 mL) in another flask. Both solutions were passed through the VFD as a continuous flow at 80°C, 7000 rpm, 45 degree tilt angle and 0.5 mL/min flow rate. After reaction the mixture was cooled to room temperature and 50 ml water was added to afford a yellow solid product of the mixture of 2,4,6, triarylpyridine (5) and chalcone (3). The crude product was purified by column chromatography over silica gel using hexane:ethylacetate (1:2) as eluent to obtain a pure product (5) as brown solid.

2.4. Characterization

3c: δH (400 MHz, d6-DMSO) 8.28 (s, 1H), 8.08 (dd, J=8.6 and 1.5 Hz, 1H), 7.96 (m, 6H),7.76 (d, J=15.6 Hz, 1H), 7.56 (m, 2H), 6.64 (d, J=8.8 Hz, 2H), 6.16 (s, 2H,

NH2). δC (100.5MHz, d6-DMSO) 186.2, 154.4, 141.8, 134.1, 133.5, 133.3, 131.6, 130.3, 128.8, 128.8, 128.1,127.5, 127.1, 125.8, 124.9, 123.2, 113.2; m.p. 175 °C.

3d: δH (400 MHz, d6-DMSO) 7.89 (d, J=8.8 Hz, 2H), 7.67 (d, J=15.4 Hz, 1H), 7.53 (d, J=15.4Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.19 (dd, J=2.0 and 8.2 Hz, 1H), 6.8 (d,

J=8.2 Hz, 1H), 6.61(d, J=8.8 Hz, 2H), 6.07 (s, 2H, NH2), 3.86 (s, 3H, OCH3). δC (100.5

MHz, d6-DMSO) 186.3,154.0, 149.4, 148.4, 131.3, 127.2, 126.1, 123.9, 119.4, 115.9, 113.1, 56.2 ; m.p. 220 °C.

4c: δH (400 MHz, d6-DMSO) 7.76 (m, 4H), 7.65 (d, J= 8.8 Hz, 2H), 7.48 (dd, J= 8.6

Chapter 5 Online Support Information for Published Articles and 1.5Hz, 1H), 7.38 (m, 2H), 6.5 (d, J= 8.8 Hz, 4H), 5.97 (s, 4H, NH2). δC (100.5

MHz, d6-DMSO)196.1, 154.0, 142.9, 133.4, 132.2, 131.0, 131.0, 127.8, 127.8, 127.0, 126.2, 126.1, 125.6,125.1, 112.9, 43.9, 38.1; m.p. 188 °C.

5c: δH (400 MHz, d6-DMSO) 8.54 (s, 1H), 8.0-8.1 (m, 7H), 7.96 (d, J= 8.3 Hz, 1H),

7.92 (s,2H, Py-H), 7.55 (m, 2H), 6.68 (J= 7.9 Hz, 4H), 5.4 (s, 4H, NH2). δC (100.5

MHz, d6-DMSO)157.1, 150.3, 148.8, 136.2, 133.7, 133.4, 128.9, 128.9, 128.2, 128.0, 127.1, 127.0, 126.9,126.6, 125.4, 114.1, 113.3 ; m.p. 170 °C.

5d: δH (400 MHz, d6-DMSO) 7.99 (d, J=8.2 Hz, 4H), 7.73 (s, 2H, Py-H), 7.43 (d, J=2 Hz,1H), 7.37 (dd, J=2 and 8.9 Hz, 1H), 6.9 (d, J=8.2 Hz,1H), 6.67 (d, J=8.2 Hz,

4H), 5.38 (s, 4H,NH2), 3.92 (s, 3H, OCH3). δC (100.5 MHz, d6-DMSO) 156.8, 149.1, 148.4, 148.1, 130.1,128.1, 127.2, 120.3, 116.2, 114.0, 112.6, 111.5, 56.4; m.p. 178 °C.

The 1H and 13C NMR data of 3a, 3b, 4a, 4b, 5a, 5b and 6a were consistent with all 1-3 literature values.

References

1. N. M. Smith, B. Corry, K. S. Iyer, M. Norret, & C. L. Raston, Lab Chip, 2009, 9, 2021-2025.

2. N. M. Smith, C. L. Raston, C. B. Smith, & A. N. Sobolev, Green Chem., 2007, 9, 1185-1190.

3. N. M. Smith, S. Pengkai, A. Nithiananthan, M. Norret, G. A. Stewart, & C. L. Raston, New J. Chem., 2009, 33, 1869-1873.

Chapter 5 Online Support Information for Published Articles 1 H NMR spectrum of 3c

13 C NMR spectrum of 3c

Chapter 5 Online Support Information for Published Articles 1 H NMR spectrum of 3d

13 C NMR spectrum of 3d

Chapter 5 Online Support Information for Published Articles 1 H NMR spectrum of 4c

13 C NMR spectrum of 4c

Chapter 5 Online Support Information for Published Articles 1 H NMR spectrum of 5c

13 C NMR spectrum of 5c

Chapter 5 Online Support Information for Published Articles 1 H NMR spectrum of 5d

13 C NMR spectrum of 5d

Chapter 5 Online Support Information for Published Articles 5.2 Supporting information for “Thin film microfluidic synthesis of fluorescent highly substituted pyridines”

1. General Information

Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. UV grade DMSO (Sigma-Aldrich) was used for all fluorescence experiments. 1H NMR spectra were recorded on a Varian spectrometer at 400 MHz and 13C NMR spectra at 100 MHz. Column chromatography was carried out on silica gel and thin layer chromatography was conducted with Silica gel 60 F254. Fluorescence spectra were recorded on a Varian Cary Eclipse fluorescence spectrophotometer. Excitation ranges of 200-450 nm and emission wavelengths of 300-600 nm were used, respectively, with 5 mm slit openings and a scan rate of 600 nm/s. Plots were displayed as excitation on the y- axis and emission on the x-axis. Mass spectra were recorded with a Waters LCT

Premier XE spectrometer, using the API method, with MeCN:H2O (9:1) as a matrix.

The crystal data for 6d are summarized in Table 1 with the structure depicted in the main text, where ellipsoids have been drawn at the 50% probability level. Crystallographic data for the structure were collected at 100(2) K on an Oxford Diffraction Xcalibur diffractometer fitted with Mo Kα radiation. Following multi- scan absorption corrections and solution by direct methods, the structure was refined against F2 with full-matrix least-squares using the program SHELXL-97.1 All Hydrogen atoms were added at calculated positions and refined by use of a riding model with isotropic displacement parameters based on those of the parent atom. Anisotropic displacement parameters were employed for the non-hydrogen atoms. Crystallographic data (excluding structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 972818. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail:[email protected]).

Chapter 5 Online Support Information for Published Articles 2. Typical procedure for preparation of polysubstituted pyridines

(3a-e):

A mixture of 1-indanone 1 (1 mmol), aldehyde 2a-e (0.5 mmol) and ammonium acetate (2 mmol) in 1 mL PEG300, was stirred for ≤ 1 minute at 80°C in a round bottom flask until all the reagents dissolved. The mixture was immediately placed in a glass tube and treated under confined mode in the VFD at 100°C, 7000 rpm and 45° tilt angle for 30 minutes. After cooling, the reaction mixture was diluted with water (25 mL) and the resulting precipitate was collected by filtration. The solid product was washed with water and EtOH and subsequently dried and then recrystallized from EtOH.

3. Typical procedure for preparation of 2,4,6-triarylpyridines (6a-e):

In a 25 mL round bottom flask, 4-(dimethylamino)benzaldehyde 4 (0.5 mmol), acetophenone 5a-e (1 mmol), and ammonium acetate (2 mmol) was stirred in PEG300 (1.0 mL) at 80°C. When all the reactants dissolved, which takes ≤ 1 minute, the solution was immediately transferred to a glass tube and treated under confined mode in the VFD at 100°C, 7000 rpm and 45° tilt angle for 30 minutes. After this time the mixture was cooled to room temperature. The reaction was then quenched with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous MgSO4 and then evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford the corresponding pyridines 6a-e.

Chapter 5 Online Support Information for Published Articles 4. NMR spectroscopic data for compounds

1 3a: H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.09 (d, 2H, J = 7.4 Hz), 7.62 (d, 4H, J = 8.5 Hz),7.52-7.40 (m, 4H), 6.96 (d, 2H, J = 8.5 Hz), 3.95 (s, 4H). 13C NMR

(DMSO-d6) δ 159.7,158.1 144.7, 143.4, 141.2, 133.8, 130.5, 128.7, 127.5, 127.4, 125.8, 120.7, 115.9, 34.3. HR- MS m/z 348.1399 (M+H)+ requires 348.1388.

N 3b

1 3b: H NMR (DMSO-d6) δ 8.39 (s, 1H), 8.14 (t, 3H, J = 7.8 Hz), 8.06 (q, 2H, J = .4 Hz),7.93 (d, 1H, J = 8.5 Hz), 7.63 (t, 4H, J = 7.7 Hz), 7.52 (t, 2H, J = 7.4 Hz), 7.46 13 (t, 2H, J = 7.2Hz), 4.03 (s, 4H). C NMR (DMSO-d6) δ 159.8, 144.7, 143.4, 141.0, 134.4, 134.0, 133.5,133.1, 128.9, 128.8, 128.7, 128.3, 128.1, 127.6, 126.8, 125.9, 120.8, 34.2. HR-MS m/z 382.1586 (M+H)+ requires 382.1596.

OCH3

3c: 1H NMR and 13C NMR spectroscopic data were consistent with the literature.2

Chapter 5 Online Support Information for Published Articles

OCH3 OH

N 3d

3d: 1H NMR (DMSO-d6) δ 9.22 (s, 1H), 8.10 (d, 2H, J = 7.2 Hz), 7.63 (d, 2H, J = 7.2 Hz),7.52-7.40 (m, 5H), 7.17 (s, 1H), 7.10 (d, 1H, J = 7.9 Hz), 3.94 (s, 4H), 3.88 (s, 13 3H). C NMR(DMSO-d6) δ 159.7, 148.3, 147.0, 144.6, 143.4, 141.2, 133.7, 129.4, 128.7, 127.5, 125.9,120.7, 120.2, 116.2, 112.8, 56.1, 34.3. HR-MS m/z 378.1489 (M+H)+ requires 378.1494.

N 3e

1 3e: H NMR (DMSO-d6) δ 8.06 (d, 2H, J = 7.4 Hz), 7.61 (t, 4H, J = 8.9 Hz), 7.50-7.37 (m, 4H), 6.86 (d, 2H, J = 8.8 Hz), 3.96 (s, 4H), 2.98 (s, 6H). 13C NMR

(DMSO-d6) δ 159.7, 151.2, 144.7, 143.6, 141.3, 133.6, 130.0, 128.6, 127.5, 125.8, 124.0, 120.7, 112.5, 34.5, 18.2. HR-MS m/z 413.1420 (M+K)+ requires 413.1420.

Chapter 5 Online Support Information for Published Articles

O2N 6a NO2

6a: 1H NMR and 13C NMR spectroscopic data were consistent with the literature.3

O2N NO2 N

1 6b: H NMR (DMSO-d6) δ 9.10 (s, 2H), 8.80 (d, 2H, J = 7.8 Hz), 8.39 (s, 2H), 8.34 (dd, 2H, J = 2.5, 8.2 Hz), 8.04 (d, 2H, J = 8.7 Hz), 7.86 (t, 2H, J = 7.9 Hz), 6.87 (d, 13 2H, J = 8.7 Hz), 3.02 (s, 6H). C NMR (DMSO-d6) δ 154.6, 148.9, 140.8, 133.7, 130.8, 128.7, 124.2, 123.8, 121.7, 116.9, 112.6, 112.5, 112.1, 70.1. HR-MS m/z 441.1541 (M+H)+ requires 441.1563.

O 6c O

1 6c: H NMR (DMSO-d6) δ 8.21 (d, 4H, J = 8.3 Hz), 7.93 (s, 2H), 7.86 (d, 2H, J = 85

Chapter 5 Online Support Information for Published Articles

13 8.3 Hz), 6.81 (d, 2H, J = 8.7 Hz), 3.81 (s, 6H, -OCH3), 2.96 (s, 6H, -CH3). C NMR

(DMSO-d6) δ 160.5, 156.2, 132.1, 129.2, 128.6, 128.3, 125.0, 114.4, 114.3, 113.9, 112.7, 55.9, 55.7. HR-MS m/z 411.2067 (M+H)+ requires 411.2073.

1 6d: H NMR (DMSO-d6) δ 8.18 (d, 4H, J = 7.8 Hz), 8.02 (s, 2H), 7.89 (d, 2H, J = 8.8 Hz),7.33 (d, 4H, J = 7.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 2.99 (s, 6H), 2.38 13 (s, 6H). C NMR (DMSO-d6) δ 156.6, 151.5, 149.6, 138.9, 136.8, 129.7, 128.3, 127.1, 124.9, 114.7, 112.7,40.8, 21.3. HR-MS m/z 401.2000 (M+Na)+ requires 401.1994.

H2N 6e NH2

6e: 1H NMR and 13C NMR spectroscopic data were consistent with the literature.4

Chapter 5 Online Support Information for Published Articles 5. Copies of 1H NMR and 13C NMR spectra 1H NMR spectrum of 3a

13C NMR spectrum of 3a

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 3b

13C NMR spectrum of 3b

Chapter 5 Online Support Information for Published Articles

1H NMR spectrum of 3d

13C NMR spectrum of 3d

Chapter 5 Online Support Information for Published Articles

1H NMR spectrum of 3e

13C NMR spectrum of 3e

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 6b

13C NMR spectrum of 6b

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 6c

13C NMR spectrum of 6c

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 6d

13C NMR spectrum of 6d

Chapter 5 Online Support Information for Published Articles 6. Crystal data and structure refinement for 6d.

Empirical formula C27H26N2 Formula weight 378.50

Temperature 100(2) K

Wavelength 0.71073 Å

Crystal system Monoclinic

Space group P21/c

Unit cell dimensions a = 7.4217(3) Å b = 23.8402(8) Å c = 11.7942(4) Å = 99.776(4)°

Volume 2056.50(13) Å3

Z 4

Density (calculated) 1.222 Mg/m3

µ 0.071 mm-1

Crystal size 0.50 x 0.23 x 0.20 mm3

θ range for data collection 2.78 to 26.00°

Index ranges -9<=h<=9, -29<=k<=20, -14<=l<=13

Reflections collected 13457

Independent reflections 4047 [R(int) = 0.0428]

Completeness to θ = 26.00° 99.9 %

Absorption correction Semi-empirical from equivalents

Max./min. transmission 1.00/0.76

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4047 / 0 / 266

Goodness-of-fit on F2 1.143

Final R indices [I>2σ(I)] R1 = 0.0824, wR2 = 0.1897

R indices (all data) R1 = 0.1015, wR2 = 0.2007

Largest diff. peak and hole 0.383 and -0.209 e.Å-3

Chapter 5 Online Support Information for Published Articles 7. Fluorescence spectra for compounds

Chapter 5 Online Support Information for Published Articles

8. References

1. G. M. Sheldrick, Acta Cryst., 2008, A64, 112-122.

2. S. Tu, T. Li, F. Shi, Q. Wang, J. Zhang, J. Xu, X. Zhu, X. Zhang, S. Zhu and D. Shi, Synthesis, 2005, 3045-3050.

3. S. Nazari and M. Shabanian, Des. Monomers Polym., 2013, 1-7. 4. M. Smith, B. Corry, I. K. Swaminathan, M. Norret and C. L. Raston, Lab Chip, 2009, 9, 2021-2025.

Chapter 5 Online Support Information for Published Articles 5.3 Supporting information for “Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films”

1. General Experimental All commercially obtained chemicals were used without any further purification unless otherwise stated. Resorcinol and pyrogallol were obtained from Sigma-Aldrich and Fluka, respectively. Acetaldehyde, butyryldehyde, heptaldehyde, benzaldehyde and vanillin were purchased from Sigma, Fluka, Fluka, Univar and Unilab respectively. Thin layer chromatography (TLC) was conducted with Silica gel 60 1 13 F254. Visualization of products was effected by ultraviolet light (254 nm). H and C NMR spectra were recorded on Varian NMR spectrometer at 400 MHz and 100 MHz, respectively. Mass spectra were recorded with a Waters LCT Premier XE spectrometer, run in W-mode, using the ESI method, with MeCN:H2O (9:1) as a matrix.

2. Synthesis

2.1 General route for the synthesis of calix[4]arens (4a-i) using VFD

To a solution of resorcinol (2.5 mmol) or pyrogallol (2.5 mmol) in ethanol (2.5 ml), the respective aldehyde (2.5 mmol) was added. Hydrochloric acid (0.125 mL, 10 M) was then added and the solution was stirred at ambient temperature for 5 mins and was passed through the VFD. The temperature, rotational speed, angle of inclination and flow rate of the VFD were fixed at respectively 800C, 7,000 rpm, 45° inclination angle and 1 mL/min. Only one feed jet was used for passing the solution into the glass tube. After one pass, water (50 mL) was added and the precipitate was collected by vacuum filtration. The product was further purified by recrystallisation from ethanol to give the calixarenes 4a-i as light brown solids.

Chapter 5 Online Support Information for Published Articles 2.2 Synthesis of predominant C4v isomer of 4h from the mixture of C4v and C2h isomers of 4h:

To a solution of the mixture of C4v and C2h isomers of 4h (1 mmol) in ethanol (1 mL), hydrochloric acid (0.1 mL, 10 M) was added (for acetic acid 0.1 mL, 17 M and 4-toluenesulfonic acid 1 mmol). It was rotated under confined mode of the VFD at 7000 rpm, 60°C and 45° inclination angle for one hour. Completion of the reaction was confirmed by 1H NMR (400 MHz) spectroscopy. The precipitate was collected by vacuum filtration and the product was further purified by recrystallisation from ethanol and obtained as a light brown solid, with mass return being obtained.

3. Characterization of calix[4]arenes (4a-i)

4a: 32%. 13C and 1H NMR spectra of this compound were similar to that found in the 1 literature.

4b: 43%. 13C and 1H NMR spectra of this compound were similar to that found in the 2 literature.

4c: 40%. 13C and 1H NMR spectra of this compound were similar to that found in the literature.3

4d: 42%. 13C and 1H NMR spectra of this compound were similar to that found in the literature.4

4e: 42%. 13C and 1H NMR spectra of this compound were similar to that found in the literature.5

4f: 75%. 13C and 1H NMR spectra of this compound were similar to that found in the literature.6

4g: 56%. 13C and 1H NMR spectra of this compound were similar to that found in the literature.2

13 1 4h (C2h): C and H NMR spectra of this compound were similar to that found in

Chapter 5 Online Support Information for Published Articles the literature.7

4h (C4v): 92%. δH (400 MHz, d6-DMSO) 3.4 (s, 12H, -OCH3), 5.59 (s, 4H, bridging –CH), 6.1-6.4 (m, 20H, ArH), 8.15 (s, 4H, -OH of pendant arms), 8.42 (s,

8H, -OH of the core). δC (100.5 MHz, d6-DMSO) 152.8, 147.0, 144.0, 137.4, 121.4, 121.2, 114.6, 113.2, 102.5, 54.5. HR-MS m/z 977.3056 (M+H)+ requires 977.3021.

4i (C2v): 84%. δH (400 MHz, d6-DMSO) 3.42 (s, 12H, -OCH3), 5.54 (s, 4H, bridging –CH), 5.57 (s, 2H, pyrogallol-H), 6.04 (s, 2H, pyrogallol-H), 6.07 (d, J=1.77 Hz, 2H, ArH), 6.09 (d, J=1.77 Hz, 2H, ArH), 6.15 (d, J=1.74 Hz, 4H, ArH), 6.29 (s, 2H, ArH), 6.32 (s, 2H, ArH), 7.25 (s, 4H, -OH of the pendant arms), 7.48 (s, 4H, -OH of the core), 7.66 (s, 2H, -OH of the core), 7.73 (s, 2H, -OH of the core), 7.95 (s, 4H, -OH of the core). δC (100.5 MHz, d6-DMSO) 146.7, 143.9, 142.1, 141.6, 135.1, 132.3, 131.9, 123.0, 122.2, 121.9, 121.5, 119.3, 114.4, 113.6, 55.6. HR-MS m/z 1041.2844 (M+H)+ requires 1041.2817.

100

Chapter 5 Online Support Information for Published Articles

1 H NMR spectrum of 4h (C4v)

13 C NMR spectrum of 4h (C4v)

101

Chapter 5 Online Support Information for Published Articles

1 H NMR spectrum of 4i (C2v)

13 C NMR spectrum of 4i (C2v)

102

Chapter 5 Online Support Information for Published Articles

4. References 1. A. G. S. Hoegberg, J. Org. Chem., 1980, 45, 4498-4500.

2. L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant, J. C. Sherman, R. C. Helgeson, C. B. Knobler and D. J. Cram, J. Org. Chem., 1989, 54, 1305-1312.

3. E. E. Dueno and K. S. Bisht, Tetrahedron, 2004, 60, 10859-10868.

4. G. Cometti, E. Dalcanale, A. Du Vosel and A.-M. Levelut, Chem. Commun., 1990, 163-165.

5. R. M. McKinlay, P. K. Thallapally, G. W. V. Cave and J. L. Atwood, Angew. Chem., Int. Ed., 2005, 44, 5733-5736.

6. S. J. Dalgarno, J. Antesberger, R. M. McKinlay and J. L. Atwood, Chem. Eur. J., 2007, 13, 8248-8255.

7. K. N. Rose, M. J. Hardie, J. L. Atwood and C. L. Raston, J. Supramol. Chem., 2001, 1, 35-38.

103

Chapter 5 Online Support Information for Published Articles 5.4 Supporting information for “Vortex fluidic promoted Diels-Alder reactions in aqueous medium”

1. Materials and methods

1H and 13C NMR spectra were recorded on Varian NMR spectrometer at 400 MHz and 100 MHz respectively. Reagents and solvents were purchased from Sigma-Aldrich, Alfa-Aesar and TCI Co. Ltd. Uncertainties of Figure 1 were calculated based on the standard deviation of the mean of three measurements.

2. Synthesis of 9, 10-Diels-Alder adduct (3) using a vortex fluidic device (VFD)

In a 10 mm NMR glass tube the 9-substituted anthracene (1) and N-substituted malimide (2) (10.0 μmol each) were suspended in a 1 mL H2O/EtOH (9:1 ratio) solution. The parameters of the VFD were 5000 rpm speed, 45° tilt angle and 50°C for 30 minutes, operating in the confined mode. The colourless solid product was filtered and dried in vacuo and the formation of 9, 10-Diels-Alder adduct was confirmed by NMR spectroscopy.

3. NMR characterization

NMR spectra of 3a, 3b, 3c, 3d, 3e, 3g were similar to that found in literature1,2 and 3i is commercially available.

3f: δH (400 MHz, CDCl3) 7.38 (t, J = 7.4 Hz, 2H), 7.20-7.00 m, 9H), 6.64 (t, J=7.4 Hz, 2H), 4.76 (d, J=3.3Hz, 1H), 4.29 (s, 2H, 2H), 3.28 (dd, J = 3.3Hz, 1H), 2.87 (d, J =

8.6 Hz, 1H), 2.27 (s, 3H). δC (100.5 MHz, CDCl3) 176.4, 175.7, 144.7, 142.1, 141.0, 138.6, 134.9, 128.3, 127.5, 127.2, 126.9, 126.8, 126.5, 126.4, 124.8, 123.7, 122.1, 121.9, 50.5, 48.4, 45.3, 44.9, 41.9, 15.3.

104

Chapter 5 Online Support Information for Published Articles

3h: δH (400 MHz, CDCl3) 7.38 (t, J = 7.4 Hz, 2H), 7.27 (d, J = 7.1 Hz, 2H), 7.18 (m, 4H), 4.76 (d, J = 3.3 Hz, 1H), 3.23 (dd, J = 3.3, 5.1 Hz, 1H), 3.05 (t, J = 7.6 Hz, 2H),

2.81 (d, J = 8.4 Hz, 1H), 2.29 (s, 3H), 0.82 (m, 2H), 0.49 (t, J = 7.4 Hz, 3H). δC (100.5

MHz, CDCl3) 176.7, 176.1, 144.6, 141.9, 141.2, 138.8, 126.8, 126.6, 126.4, 124.9, 123.7, 122.1, 121.9, 50.3, 48.2, 45.5, 44.9, 39.9, 20.3, 15.2, 10.9.

4. References

1. M. Yoshizawa, M. Tamura and M. Fujita, Science, 2006, 312, 251-254.

2. S. Horiuchi, T. Murase and M. Fujita, Chem. Asian J., 2011, 6, 1839-1847.

105

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 3f

13C NMR spectrum of 3f

106

Chapter 5 Online Support Information for Published Articles 1H NMR spectrum of 3h

13C NMR spectrum of 3h

107

Chapter 6 References 6. References

(1) Lutze, P.; Gani, R.; Woodley, J. M.: Process intensification: A perspective on process synthesis. Chemical Engineering and Processing: Process Intensification 2010, 49, 547-558. (2) Ponce-Ortega, J. M.; Al-Thubaiti, M. M.; El-Halwagi, M. M.: Process intensification: New understanding and systematic approach. Chemical Engineering and Processing: Process Intensification 2012, 53, 63-75. (3) Stankiewicz, A.; Moulin, J.: Process intensification. Chemical Engineering Progress 2000, 22-34. (4) Reay, D.; Ramshaw, C.; Harvey, A.: Process Intensification: Engineering for efficiency, sustainability and flexibility; Butterworth-Heinemann, 2013. (5) Reay, D.; Ramshaw, C.; Harvey, A.: Process Intensification: Engineering for efficiency, sustainability and flexibility; Butterworth-Heinemann, 2013. (6) Seeberger, P. H.: Organic synthesis: Scavengers in full flow. Nature Chemistry 2009, 1, 258-260. (7) Jachuk, R. J.; Ramshaw, C.; Boodhoo, K.; Dalgleish, J. C.: Process Intensification: The Opportunity Presented by Spinning Disc Reactor Technology in Institute of Chemical Engineering Symposium Ser 1997; Vol. 141; pp 417-424. (8) Fell, N.; Ramshaw, C.: Innovation Offers a New Spin on Drug Production. TCE 1997, 656, 23-25. (9) Cafiero, L.; Baffi, G.; Chianese, A.; Jachuck, R.: Process intensification: precipitation of barium sulfate using a spinning disk reactor. Industrial & Engineering Chemistry Research 2002, 41, 5240-5246. (10) Aoune, A.; Ramshaw, C.: Process intensification: heat and mass transfer characteristics of liquid films on rotating discs. International Journal of Heat and Mass Transfer 1999, 42, 2543-2556. (11) Jachuck, R.; Ramshaw, C.: Process intensification: Heat transfer characteristics of tailored rotating surfaces. Heat Recovery Systems and CHP 1994, 14, 475-491. (12) Swaminathan Iyer, K.; Norret, M.; Dalgarno, S. J.; Atwood, J. L.; Raston, C. L.: Loading Molecular Hydrogen Cargo within Viruslike Nanocontainers. Angewandte Chemie International Edition 2008, 47, 6362-6366.

108

Chapter 6 References (13) Oxley, P.; Brechtelsbauer, C.; Ricard, F.; Lewis, N.; Ramshaw, C.: Evaluation of spinning disk reactor technology for the manufacture of pharmaceuticals. Industrial & Engineering Chemistry Research 2000, 39, 2175-2182. (14) Boodhoo, K.; Dunk, W.; Jachuck, R.: Influence of centrifugal field on free‐radical polymerization kinetics. Journal of Applied Polymer Science 2002, 85, 2283- 2286. (15) Leveson, P.; Dunk, W.; Jachuck, R.: Numerical investigation of kinetics of free‐radical polymerization on spinning disk reactor. Journal of Applied Polymer Science 2003, 90, 693-699. (16) Boodhoo, K.; Jachuck, R.: Process intensification: spinning disc reactor for condensation polymerisation. Green Chemistry 2000, 2, 235-244. (17) Trippa, G.; Hetherington, P.; Jachuck, R.: Process intensification: Precipitation of calcium carbonate from the carbonation reaction of lime water using a spinning disc reactor. In 15th Int. Symp. Ind. Cryst., Sorrento, Italy, 2002. (18) Iyer, K. S.; Raston, C. L.; Saunders, M.: Hierarchical aqueous self-assembly of C60 nano-whiskers and C60-silver nano-hybrids under continuous flow. Lab on a Chip 2007, 7, 1121-1124. (19) Chin, S. F.; Iyer, K. S.; Raston, C. L.: Fabrication of carbon nano-tubes decorated with ultra fine superparamagnetic nano-particles under continuous flow conditions. Lab on a Chip 2008, 8, 439-442. (20) Chin, S. F.; Iyer, K. S.; Raston, C. L.; Saunders, M.: Size selective synthesis of superparamagnetic nanoparticles in thin fluids under continuous flow conditions. Advanced Functional Materials 2008, 18, 922-927. (21) Anantachoke, N.; Makha, M.; Raston, C. L.; Reutrakul, V.; Smith, N. C.; Saunders, M.: Fine tuning the production of nanosized β-carotene particles using spinning disk processing. Journal of the American Chemical Society 2006, 128, 13847-13853. (22) Hartlieb, K. J.; Martin, A. D.; Saunders, M.; Raston, C. L.: Photochemical generation of small silver nanoparticles involving multi-functional phosphonated calixarenes. New Journal of Chemistry 2010, 34, 1834-1837. (23) Hartlieb, K. J.; Raston, C. L.; Saunders, M.: Controlled scalable synthesis of ZnO nanoparticles. Chemistry of Materials 2007, 19, 5453-5459. (24) Vicevic, M.; Jachuck, R.; Scott, K.; Clark, J.; Wilson, K.: Rearrangement of α- pinene oxide using a surface catalysed spinning disc reactor (SDR). Green Chemistry 2004, 6, 533-537. 109

Chapter 6 References (25) Smith, N. M.; Corry, B.; Swaminathan, I. K.; Norret, M.; Raston, C. L.: A microfluidic platform to synthesise a G-quadruplex binding ligand. Lab on a Chip 2009, 9, 2021-2025. (26) Smith, N. M.; Raston, C. L.; Smith, C. B.; Sobolev, A. N.: PEG mediated synthesis of amino-functionalized 2,4,6-triarylpyridines. Green Chemistry 2007, 9, 1185-1190. (27) Jachuck, R. J. J.; Ramshaw, C.: Rotating surface of revolution reactor with feed and collection mechanisms. Google Patents, US7014820, 2001. (28) Lodha, H.; Jachuck, R.; Suppiah Singaram, S.: Intensified Biodiesel Production Using a Rotating Tube Reactor. Energy & Fuels 2012, 26, 7037-7040. (29) Dev, S.; Iyer, K. S.; Raston, C. L.: Nanosized drug formulations under microfluidic continuous flow. Lab on a Chip 2011, 11, 3214-3217. (30) Dev, S.; Prabhakaran, P.; Filgueira, L.; Iyer, K. S.; Raston, C. L.: Microfluidic fabrication of cationic curcumin nanoparticles as an anti-cancer agent. Nanoscale 2012, 4, 2575-2579. (31) Dev, S.; Toster, J.; Vadhan Prasanna, S.; Fitzgerald, M.; Swaminathan Iyer, K.; Raston, C. L.: Suppressing regrowth of microfluidic generated drug nanocrystals using polyelectrolyte coatings. RSC Advances 2013, 3, 695-698. (32) Fang, J.; Evans, C. W.; Willis, G. J.; Sherwood, D.; Guo, Y.; Lu, G.; Raston, C. L.; Iyer, K. S.: Sequential microfluidic flow synthesis of CePO4 nanorods decorated with emission tunable quantum dots. Lab on a Chip 2010, 10, 2579- 2582. (33) Fang, J.; Guo, Y.; Lu, G.; Raston, C. L.; Iyer, K. S.: Instantaneous crystallization of ultrathin one-dimensional fluorescent rhabdophane nanowires at room temperature. Green Chemistry 2011, 13, 817-819. (34) Raston, C. L.: Thin film tube reactor. Google Patents, US20130289282, 2011. (35) Chen, X.; Dobson, J. F.; Raston, C. L.: Vortex fluidic exfoliation of graphite and boron nitride. Chemical Communications 2012, 48, 3703-3705. (36) Wahid, M. H.; Eroglu, E.; Chen, X.; Smith, S. M.; Raston, C. L.: Functional multi-layer graphene-algae hybrid material formed using vortex fluidics. Green Chemistry 2013, 15, 650-655. (37) Martin, A. D.; Boulos, R. A.; Hubble, L. J.; Hartlieb, K. J.; Raston, C. L.: Multifunctional water-soluble molecular capsules based on p-phosphonic acid calix[5]arene. Chemical Communications 2011, 47, 7353-7355.

110

Chapter 6 References (38) Yasin, F. M.; Boulos, R. A.; Hong, B. Y.; Cornejo, A.; Iyer, K. S.; Gao, L.; Chua, H. T.; Raston, C. L.: Microfluidic size selective growth of palladium nanoparticles on carbon nano-onions. Chemical Communications 2012, 48, 10102- 10104. (39) Chen, X.; Yasin, F. M.; Eggers, P. K.; Boulos, R. A.; Duan, X.; Lamb, R. N.; Iyer, K. S.; Raston, C. L.: Non-covalently modified graphene supported ultrafine nanoparticles of palladium for hydrogen gas sensing. RSC Advances 2013, 3, 3213-3217. (40) Eroglu, E.; D'Alonzo, N. J.; Smith, S. M.; Raston, C. L.: Vortex fluidic entrapment of functional microalgal cells in a magnetic polymer matrix. Nanoscale 2013, 5, 2627-2631. (41) Wahid, M. H.; Eroglu, E.; Chen, X.; Smith, S. M.; Raston, C. L.: Entrapment of Chlorella vulgaris cells within graphene oxide layers. RSC Advances 2013, 3, 8180-8183. (42) Li, C.-J.; Trost, B. M.: Green chemistry for chemical synthesis. In Proceedings of the National Academy of Sciences, 2008; Vol. 105; pp 13197-13202. (43) Anastas, P. T.; Kirchhoff, M. M.: Origins, current status, and future challenges of green chemistry. Accounts of chemical research 2002, 35, 686-694. (44) H Clark, J.; EI Deswarte, F.; J Farmer, T.: The integration of green chemistry into future biorefineries. Biofuels, Bioproducts and Biorefining 2009, 3, 72-90. (45) Pohar, A.; Plazl, I.: Process intensification through microreactor application. Chemical and Biochemical Engineering Quarterly 2009, 23, 537-544. (46) Balasubramanian, M.; Keay, J.: Pyridines and their benzo derivatives: applications; Pergemon Press, New York, 1996; Vol. 5. (47) Kim, B. Y.; Ahn, J. B.; Lee, H. W.; Kang, S. K.; Lee, J. H.; Shin, J. S.; Ahn, S. K.; Hong, C. I.; Yoon, S. S.: Synthesis and biological activity of novel substituted pyridines and purines containing 2, 4-thiazolidinedione. European Journal of Medicinal Chemistry 2004, 39, 433-447. (48) Enyedy, I. J.; Sakamuri, S.; Zaman, W. A.; Johnson, K. M.; Wang, S.: Pharmacophore-based discovery of substituted pyridines as novel dopamine transporter inhibitors. Bioorganic & Medicinal Chemistry Letters 2003, 13, 513- 517. (49) Pillai, A. D.; Rathod, P. D.; PX, F.; Patel, M.; Nivsarkar, M.; Vasu, K. K.; Padh, H.; Sudarsanam, V.: Novel drug designing approach for dual inhibitors as anti-

111

Chapter 6 References inflammatory agents: implication of pyridine template. Biochemical and Biophysical Research Communications 2003, 301, 183-186. (50) Klimesova, V.; Svoboda, M.; Waisser, K.; Pour, M.; Kaustova, J.: New pyridine derivatives as potential antimicrobial agents. Farmaco (Societa chimica italiana : 1989) 1999, 54, 666-72. (51) Constable, E.: Metallodendrimers: metal ions as supramolecular glue. Chemical Communications 1997, 1073-1080. (52) Newkome, G. R.; Patri, A. K.; Holder, E.; Schubert, U. S.: Synthesis of 2, 2′‐Bipyridines: Versatile Building Blocks for Sexy Architectures and Functional Nanomaterials. European Journal of Organic Chemistry 2004, 2004, 235-254. (53) Wang, P.; Moorefield, C. N.; Newkome, G. R.: Nanofabrication: Reversible Self‐Assembly of an Imbedded Hexameric Metallomacrocycle within a Macromolecular Superstructure. Angewandte Chemie International Edition 2005, 44, 1679-1683. (54) Constable, E. C.; Dunphy, E. L.; Housecroft, C. E.; Kylberg, W.; Neuburger, M.; Schaffner, S.; Schofield, E. R.; Smith, C. B.: Structural Development of Free or Coordinated 4′-(4-Pyridyl)-2,2′:6′,2′′-terpyridine Ligands through N-Alkylation: New Strategies for Metallamacrocycle Formation. Chemistry – A European Journal 2006, 12, 4600-4610. (55) Newkome, G. R.; Wang, P.; Moorefield, C. N.; Cho, T. J.; Mohapatra, P. P.; Li, S.; Hwang, S.-H.; Lukoyanova, O.; Echegoyen, L.; Palagallo, J. A.: Nanoassembly of a Fractal Polymer: A Molecular" Sierpinski Hexagonal Gasket". Science 2006, 312, 1782-1785. (56) Kelch, S.; Rehahn, M.: Synthesis and properties in solution of rodlike, 2, 2': 6', 2''- terpyridine-based ruthenium (II) coordination polymers. Macromolecules 1999, 32, 5818-5828. (57) Lohmeijer, B. G. G.; Schubert, U. S.: Supramolecular Engineering with Macromolecules: An Alternative Concept for Block Copolymers. Angewandte Chemie International Edition 2002, 41, 3825-3829. (58) Lohmeijer, B. G.; Schubert, U. S.: Playing LEGO with macromolecules: Design, synthesis, and self‐organization with metal complexes. Journal of Polymer Science Part A: Polymer Chemistry 2003, 41, 1413-1427.

112

Chapter 6 References (59) Andres, P. R.; Schubert, U. S.: New Functional Polymers and Materials Based on 2, 2′: 6′, 2 ″‐Terpyridine Metal Complexes. Advanced Materials 2004, 16, 1043- 1068. (60) Harriman, A.; Ziessel, R.: Building photoactive molecular-scale wires. Coordination Chemistry Reviews 1998, 171, 331-339. (61) O'Regan, B.; Gratzel, M.: A low-cost, high-efficiency solar cell based on dye- sensitized colloidal TiO2 films. Nature 1991, 353, 737-740. (62) Kohle, O.; Ruile, S.; Grätzel, M.: Ruthenium (II) Charge-Transfer Sensitizers Containing 4, 4'-Dicarboxy-2, 2'-bipyridine. Synthesis, Properties, and Bonding Mode of Coordinated Thio-and Selenocyanates. Inorganic Chemistry 1996, 35, 4779-4787. (63) Schmittel, M.; Ammon, H.: Synthesis and spectroscopy of new iron (II) complexes of 4, 7-bis (aza-crown ether)-phenanthrolines with unusual complexation properties. Chemical Communications 1995, 687-688. (64) Indelli, M. T.; Bignozzi, C. A.; Scandola, F.; Collin, J.-P.: Design of long-lived Ru (II) terpyridine MLCT states. Tricyano terpyridine complexes. Inorganic Chemistry 1998, 37, 6084-6089. (65) Trawick, B. N.; Daniher, A. T.; Bashkin, J. K.: Inorganic mimics of ribonucleases and ribozymes: from random cleavage to sequence-specific chemistry to catalytic antisense drugs. Chemical Reviews 1998, 98, 939-960. (66) Zak, B.; Baginski, E. S.; Epstein, E.; Weiner, L. M.: Terosite sulfonate: A sensitive reagent for the determination of serum iron. Clinica Chimica Acta 1970, 29, 77-82. (67) Zak, B.; Baginski, E. S.; Epstein, E.; Weiner, L. M.: Determination of Serum Iron with a New Color Reagent. Clinical Toxicology 1971, 4, 621-629. (68) Liu, H.-Q.; Cheung, T.-C.; Peng, S.-M.; Che, C.-M.: Novel luminescent cyclometaiated and terpyridine gold(III) complexes and DNA binding studies. Chemical Communications 1995, 1787-1788. (69) van Vliet, P. M.; Toekimin, S. M. S.; Haasnoot, J. G.; Reedijk, J.; Nováková, O.; Vrána, O.; Brabec, V.: mer-[Ru(terpy)Cl3] (terpy = 2,2′:6′,2″-terpyridine) shows biological activity, forms interstrand cross-links in DNA and binds two guanine derivatives in a trans configuration. Inorganica Chimica Acta 1995, 231, 57-64. (70) Carter, P. J.; Cheng, C.-C.; Thorp, H. H.: Oxidation of DNA and RNA by Oxoruthenium(IV) Metallointercalators: Visualizing the Recognition Properties

113

Chapter 6 References of Dipyridophenazine by High-Resolution Electrophoresis. Journal of the American Chemical Society 1998, 120, 632-642. (71) Xu, W.-C.; Zhou, Q.; Ashendel, C. L.; Chang, C.-t.; Chang, C.-j.: Novel protein kinase C inhibitors: synthesis and PKC inhibition of β-substituted polythiophene derivatives. Bioorganic & Medicinal Chemistry Letters 1999, 9, 2279-2282. (72) Kim, D. S. H. L.; Ashendel, C. L.; Zhou, Q.; Chang, C.-t.; Lee, E.-S.; Chang, C.- j.: Novel protein kinase C inhibitors: α-terthiophene derivatives. Bioorganic & Medicinal Chemistry Letters 1998, 8, 2695-2698. (73) Zhang, Y.; Murphy, C. B.; Jones, W. E.: Poly[p-(phenyleneethynylene)-alt- (thienyleneethynylene)] Polymers with Oligopyridine Pendant Groups: Highly Sensitive Chemosensors for Transition Metal Ions. Macromolecules 2001, 35, 630-636. (74) Leonard, K. A.; Nelen, M. I.; Simard, T. P.; Davies, S. R.; Gollnick, S. O.; Oseroff, A. R.; Gibson, S. L.; Hilf, R.; Chen, L. B.; Detty, M. R.: Synthesis and evaluation of chalcogenopyrylium dyes as potential sensitizers for the photodynamic therapy of cancer. Journal of Medicinal Chemistry 1999, 42, 3953- 3964. (75) Lowe, G.; Droz, A. S.; Vilaivan, T.; Weaver, G. W.; Tweedale, L.; Pratt, J. M.; Rock, P.; Yardley, V.; Croft, S. L.: Cytotoxicity of (2, 2': 6', 2''-Terpyridine) platinum (II) Complexes to Leishmania d onovani, Trypanosoma c ruzi, and Trypanosoma b rucei. Journal of Medicinal Chemistry 1999, 42, 999-1006. (76) Bonse, S.; Richards, J. M.; Ross, S. A.; Lowe, G.; Krauth-Siegel, R. L.: (2, 2': 6', 2''-Terpyridine) platinum (II) Complexes Are Irreversible Inhibitors of Trypanosoma c ruzi Trypanothione Reductase But Not of Human Glutathione Reductase. Journal of Medicinal Chemistry 2000, 43, 4812-4821. (77) Zhao, L.-X.; Moon, Y.-S.; Basnet, A.; Kim, E.-k.; Jahng, Y.; Park, J. G.; Jeong, T. C.; Cho, W.-J.; Choi, S.-U.; Lee, C. O.; Lee, S.-Y.; Lee, C.-S.; Lee, E.-S.: Synthesis, topoisomerase I inhibition and structure–activity relationship study of 2,4,6-trisubstituted pyridine derivatives. Bioorganic & Medicinal Chemistry Letters 2004, 14, 1333-1337. (78) Han, H.; Hurley, L. H.: G-quadruplex DNA: a potential target for anti-cancer drug design. Trends in Pharmacological Sciences 2000, 21, 136-142. (79) Kelland, L. R.: Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics–current status and future prospects. European Journal of Cancer 2005, 41, 971-979. 114

Chapter 6 References (80) Chang, C.-C.; Chu, J.-F.; Kao, F.-J.; Chiu, Y.-C.; Lou, P.-J.; Chen, H.-C.; Chang, T.-C.: Verification of antiparallel G-quadruplex structure in human telomeres by using two-photon excitation fluorescence lifetime imaging microscopy of the 3, 6- Bis (1-methyl-4-vinylpyridinium) carbazole diiodide molecule. Analytical chemistry 2006, 78, 2810-2815. (81) Dexheimer, T. S.; Sun, D.; Hurley, L. H.: Deconvoluting the structural and drug- recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. Journal of the American Chemical Society 2006, 128, 5404-5415. (82) Orner, B. P.; Ernst, J. T.; Hamilton, A. D.: Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an α-helix. Journal of the American Chemical Society 2001, 123, 5382-5383. (83) Waller, Z. A. E.; Shirude, P. S.; Rodriguez, R.; Balasubramanian, S.: Triarylpyridines: a versatile small molecule scaffold for G-quadruplex recognition. Chemical Communications 2008, 1467-1469. (84) Lehmann, U.; Henze, O.; Schlüter, A. D.: 5,5″-Disubstituted 2,2′:6′,2″- Terpyridines through and for Metal-Mediated Cross-Coupling Chemistry. Chemistry – A European Journal 1999, 5, 854-859. (85) KrÖHnke, F.: The Specific Synthesis of Pyridines and Oligopyridines. Synthesis 1976, 1-24. (86) Weiss, M.: Acetic Acid—Ammonium Acetate Reactions. An Improved Chichibabin Pyridine Synthesis1. Journal of the American Chemical Society 1952, 74, 200-202. (87) Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G.: Ketenedithioacetals as synthetic intermediates. A versatile synthesis of pyridenes, polypyridinyls, and pyrylium salts. Journal of the American Chemical Society 1981, 103, 3585-6. (88) Cave, G. W.; Raston, C. L.: Toward benign syntheses of pyridines involving sequential solvent free aldol and Michael addition reactions. Chemical Communications 2000, 2199-2200. (89) Cave, G. W.; Raston, C. L.; Scott, J. L.: Recent advances in solventless organic reactions: towards benign synthesis with remarkable versatility. Chemical Communications 2001, 2159-2169. (90) Cave, G. W. V.; Raston, C. L.: Efficient synthesis of pyridines via a sequential solventless aldol condensation and Michael addition. Perkin Transaction 1 2001, 3258-3264.

115

Chapter 6 References (91) Anderson, H. L.; Walter, C. J.; Vidal-Ferran, A.; Hay, R. A.; Lowden, P. A.; Sanders, J. K.: Octatetrayne-linked porphyrins:‘stretched’cyclic dimers and trimers with very spacious cavities. Perkin Transactions 1 1995, 2275-2279. (92) Smith, C. B.; Raston, C. L.; Sobolev, A. N.: Poly(ethyleneglycol) (PEG): a versatile reaction medium in gaining access to 4'-(pyridyl)-terpyridines. Green Chemistry 2005, 7, 650-654. (93) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D.: Polyethylene glycol and solutions of polyethylene glycol as green reaction media. Green Chemistry 2005, 7, 64-82. (94) Winter, A.; van den Berg, A. M. J.; Hoogenboom, R.; Kickelbick, G.; Schubert, U. S.: A Green and Straightforward Synthesis of 4′-Substituted Terpyridines. Synthesis 2006, 2873-2878. (95) Tamami, B.; Yeganeh, H.: Synthesis and characterization of novel aromatic polyamides derived from 4-aryl-2, 6-bis (4-aminophenyl) pyridines. Polymer 2001, 42, 415-420. (96) Iyer, K. S.; Raston, C. L.; Saunders, M.: Continuous flow nano-technology: manipulating the size, shape, agglomeration, defects and phases of silver nanoparticles. Lab on a Chip 2007, 7, 1800-5. (97) Tu, S.; Li, T.; Shi, F.; Wang, Q.; Zhang, J.; Xu, J.; Zhu, X.; Zhang, X.; Zhu, S.; Shi, D.: A convenient one-pot synthesis of 4'-aryl-2,2':6',2''-terpyridines and 2,4,6- triarylpyridines under microwave irradiation. Synthesis 2005, 3045-3050. (98) Tu, S.; Jia, R.; Jiang, B.; Zhang, J.; Zhang, Y.; Yao, C.; Ji, S.: Kröhnke reaction in aqueous media: one-pot clean synthesis of 4′-aryl-2, 2′: 6′, 2 ″-terpyridines. Tetrahedron 2007, 63, 381-388. (99) Yin, G.; Liu, Q.; Ma, J.; She, N.: Solvent-and catalyst-free synthesis of new hydroxylated trisubstituted pyridines under microwave irradiation. Green Chemistry 2012, 14, 1796-1798. (100) Satasia, S. P.; Kalaria, P. N.; Raval, D. K.: Acidic ionic liquid immobilized on cellulose: an efficient and recyclable heterogeneous catalyst for the solvent-free synthesis of hydroxylated trisubstituted pyridines. RSC Advances 2013, 3, 3184- 3188. (101) Behmadi, H.; Naderipour, S.; Saadati, S. M.; Barghamadi, M.; Shaker, M.; Tavakoli-Hoseini, N.: Solvent-free synthesis of new 2,4,6-triarylpyridines catalyzed by a Brønsted acidic ionic liquid as a green and reusable catalyst. Journal of Heterocyclic Chemistry 2011, 48, 1117-1121. 116

Chapter 6 References (102) Heravi, M. M.; Bakhtiari, K.; Daroogheha, Z.; Bamoharram, F. F.: An efficient synthesis of 2, 4, 6-triarylpyridines catalyzed by heteropolyacid under solvent-free conditions. Catalysis Communications 2007, 8, 1991-1994. (103) Shinde, P. V.; Labade, V. B.; Gujar, J. B.; Shingate, B. B.; Shingare, M. S.: Bismuth triflate catalyzed solvent-free synthesis of 2,4,6-triaryl pyridines and an unexpected selective acetalization of tetrazolo[1,5-a]-quinoline-4-carbaldehydes. Tetrahedron Letters 2012, 53, 1523-1527. (104) Mukhopadhyay, C.; Tapaswi, P. K.; Butcher, R. J.: L-Proline-catalyzed one-pot expeditious synthesis of highly substituted pyridines at room temperature. Tetrahedron Letters 2010, 51, 1797-1802. (105) Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan, Z.-H.: Copper- Catalyzed Coupling of Oxime Acetates with Aldehydes: A New Strategy for Synthesis of Pyridines. Organic Letters 2011, 13, 5394-5397. (106) Adib, M.; Tahermansouri, H.; Koloogani, S. A.; Mohammadi, B.; Bijanzadeh, H. R.: Kroehnke pyridines: An efficient solvent-free synthesis of 2,4,6- triarylpyridines. Tetrahedron Letters 2006, 47, 5957-5960.

(107) Nagarapu, L.; Peddiraju, R.; Apuri, S.: HClO4-SiO2 as a novel and recyclable catalyst for the synthesis of 2, 4, 6-triarylpyridines under solvent-free conditions. Catalysis Communications 2007, 8, 1973-1976. (108) Davoodnia, A.; Razavi, B.; Tavakoli-Hoseini, N.: An Efficient and Green Procedure for the Synthesis of 2,4,6-Triarylpyridines Using PPA-SiO2 as a Reusable Heterogeneous Catalyst Under Solvent-Free Conditions. E-Journal of Chemistry 2012, 9. (109) Gutsche, C.: Calixarenes in Monographs in Supramolecular Chemistry; Stoddart, JF, Ed; The Royal Society of Chemistry: Cambridge, UK, 1989. (110) Baeyer, A.: Ueber die Verbindungen der Aldehyde mit den Phenolen. Berichte der deutschen chemischen Gesellschaft 1872, 5, 280-282. (111) Michael, A.: American Chemical Journal 1883, 5, 338. (112) Fabre, R.: Liebigs Annalen der Chemie 1922, 18. (113) Hultzsch, K.: Chemie der Phenolharze; Springer-Verlag, 1950; Vol. 3. (114) Niederl, J. B.; Vogel, H. J.: Aldehyde-resorcinol condensations. Journal of the American Chemical Society 1940, 62, 2512-14. (115) Erdtman, H.; Hogberg, S.; Abrahamsson, S.; Nilsson, B.: Cyclooligomeric phenol-aldehyde condensation products. I. Tetrahedron Letters 1968, 1679-82.

117

Chapter 6 References (116) Gutsche, C. D.; Dhawan, B.; No, K. H.; Muthukrishnan, R.: Calixarenes. 4. The synthesis, characterization, and properties of the calixarenes from p-tert- butylphenol. Journal of the American Chemical Society 1981, 103, 3782-3792. (117) Egberink, R. J. M.; Cobben, P. L. H. M.; Verboom, W.; Harkema, S.; Reinhoudt, D. N.: Hoegberg compounds with a functionalized box-like cavity. Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 1992, 12, 151-8. (118) Cram, D. J.; Karbach, S.; Kim, H. E.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.; Helgeson, R. C.: Host-guest complexation. 46. Cavitands as open molecular vessels form solvates. Journal of the American Chemical Society 1988, 110, 2229- 2237. (119) Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Weiser, J.; Bryant, J. A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J.: Host-guest complexation. 48. Octol building blocks for cavitands and carcerands. The Journal of Organic Chemistrty 1989, 54, 1305-12. (120) Schneider, U.; Schneider, H.-J.: Synthese und Eigenschaften von Makrocyclen aus Resorcinen sowie von entsprechenden Derivaten und Wirt-Gast-Komplexen. Chemische Berichte 1994, 127, 2455-2469. (121) MacGillivray, L. R.; Atwood, J. L.: Cavity-containing materials based upon resorcin[4]arenes by discovery and design. Journal of Solid State Chemistry 2000, 152, 199-210. (122) O'Farrell, C. M.; Wenzel, T. J.: Water-soluble calix[4]resorcinarenes as chiral NMR solvating agents for phenyl-containing compounds. Tetrahedron: Asymmetry 2008, 19, 1790-1796. (123) Yonetake, K.; Nakayama, T.; Ueda, M.: New liquid crystals based on calixarenes. Journal of Materials Chemistry 2001, 11, 761-767. (124) Cometti, G.; Dalcanale, E.; Du, V. A.; Levelut, A. M.: A new, conformationally mobile macrocyclic core for bowl-shaped columnar liquid crystals. Liquid Crystals 1992, 11, 93-100. (125) Inouye, M.; Hashimoto, K.-i.; Isagawa, K.: Nondestructive detection of acetylcholine in protic media: artificial-signaling acetylcholine receptors. Journal of the American Chemical Society 1994, 116, 5517-5518. (126) Hayashida, O.; Uchiyama, M.: Rotaxane-type resorcinarene tetramers as histone- sensing fluorescent receptors. Organic and Biomolecular Chemistry 2008, 6, 3166-70.

118

Chapter 6 References (127) Sokoliess, T.; Menyes, U.; Roth, U.; Jira, T.: Separation of cis- and trans-isomers of thioxanthene and dibenz[b,e]oxepin derivatives on calixarene- and resorcinarene-bonded high-performance liquid chromatography stationary phases. Journal of Chromatography A 2002, 948, 309-319. (128) Pietraszkiewicz, O.; Pietraszkiewicz, M.: Separation of pyrimidine bases on a HPLC stationary RP-18 phase coated with calix[4]resorcinarene. Journal of Inclusion Phenomena and Macrocyclic Chemistry 1999, 35, 261-270. (129) Zakharova, L. Y.; Syakaev, V. V.; Voronin, M. A.; Valeeva, F. V.; Ibragimova, A. R.; Ablakova, Y. R.; Kazakova, E. K.; Latypov, S. K.; Konovalov, A. I.: NMR and spectrophotometry study of the supramolecular catalytic system based on polyethyleneimine and amphiphilic sulfonatomethylated calix [4] resorcinarene. The Journal of Physical Chemistry C 2009, 113, 6182-6190. (130) Pashirova, T. N.; Lukashenko, S. S.; Kosacheva, E. M.; Leonova, M. V.; Vagapova, L. I.; Burilov, A. R.; Pudovik, M. A.; Kudryavtseva, L. A.; Konovalov, A. I.: Aggregation behavior and catalytic properties of systems based on aminomethylated calix[4]resorcinarenes and poly(ethylene) imines. Russian Journal of General Chemistry 2008, 78, 402-409. (131) Jain, V. K.; Pillai, S. G.; Pandya, R. A.; Agrawal, Y. K.; Shrivastav, P. S.: Molecular octopus: octa functionalized calix[4]resorcinarene-hydroxamic acid [C4RAHA] for selective extraction, separation and preconcentration of U(VI). Talanta 2005, 65, 466-475. (132) Mustafina, A. R.; Zagidullina, I. Y.; Maslennikova, V. I.; Serkova, O. S.; Guzeeva, T. V.; Konovalov, A. I.: Liquid extraction of LaIII, GdIII, and YbIII ions by phosphorylated calix[4]resorcinarene derivatives. Russian Chemical Bulletin 2007, 56, 313-319. (133) Ichimura, K.; Fujimaki, M.; Matsuzawa, Y.; Hayashi, Y.; Nakagawa, M.: Characteristics of monolayers of calix[4]resorcinarenes derivatives having azobenzene chromophores. Materials Science and Engineering: C 1999, C8-C9, 353-359. (134) Botta, B.; Pierini, M.; Delle, M. G.; Subissati, D.; Subrizi, F.; Zappia, G.: Synthesis of amino and ammonium resorcin[4]arenes as potential receptors. Synthesis 2008, 2110-2116. (135) Dalgarno, S. J.; Cave, G. W. V.; Atwood, J. L.: Toward the isolation of functional organic nanotubes. Angewandte Chemie International Edition 2006, 45, 570-574.

119

Chapter 6 References (136) Misra, T. K.; Liu, C.-Y.: Synthesis, isolation, and redispersion of resorcinarene- capped anatase TiO< sub> 2 nanoparticles in nonaqueous solvents. Journal of Colloid and Interface Science 2007, 310, 178-183. (137) Ehrler, S.; Pieles, U.; Wirth-Heller, A.; Shahgaldian, P.: Surface modification of resorcinarene based self-assembled solid lipid nanoparticles for drug targeting. Chemical Communications 2007, 2605-2607. (138) Hoegberg, A. G. S.: Two stereoisomeric macrocyclic resorcinol-acetaldehyde condensation products. The Journal of Organic Chemistrty 1980, 45, 4498-500. (139) Hoegberg, A. G. S.: Cyclooligomeric phenol-aldehyde condensation products. 2. Stereoselective synthesis and DNMR study of two 1,8,15,22- tetraphenyl[14]metacyclophan-3,5,10,12,17,19,24,26-octols. Journal of the American Chemical Society 1980, 102, 6046-50. (140) Timmerman, P.; Verboom, W.; Reinhoudt, D. N.: Resorcinarenes. Tetrahedron 1996, 52, 2663-704. (141) Jain, V.; Kanaiya, P.: Chemistry of calix [4] resorcinarenes. Russian Chemical Reviews 2011, 80, 75-102. (142) Weinelt, F.; Schneider, H. J.: Host-guest chemistry. 27. Mechanisms of macrocycle genesis. The condensation of resorcinol with aldehydes. Journal of Organic Chemistrty 1991, 56, 5527-35. (143) Roberts, B. A.; Cave, G. W. V.; Raston, C. L.; Scott, J. L.: Solvent-free synthesis of calix[4]resorcinarenes. Green Chemistry 2001, 3, 280-284. (144) Konishi, H.; Morikawa, O.: Conformational properties of octahydroxy[1.4]metacyclophanes with unsubstituted methylene bridges. Chemical Communications 1993, 34-35. (145) Botta, B.; Di Giovanni, M. C.; Monache, G. D.; De Rosa, M. C.; Gacs-Baitz, E.; Botta, M.; Corelli, F.; Tafi, A.; Santini, A.: A novel route to calix [4] arenes. 2. Solution-and solid-state structural analyses and molecular modeling studies. The Journal of Organic Chemistry 1994, 59, 1532-1541. (146) Benedetti, E.; Pedone, C.; Iacovino, R.; Botta, B.; Delle Monache, G.; De Rosa, M. C.; Botta, M.; Corelli, F.; Tafi, A.; Santini, A.: Journal of Chemical Research 1994, 476-477. (147) Iwanek, W.; Syzdol, B.: Lewis Acid-Induced Synthesis of Octamethoxyresorcarenes. Synthetic Communications 1999, 29, 1209-1216.

120

Chapter 6 References (148) Moore, D.; Watson, G. W.; Gunnlaugsson, T.; Matthews, S. E.: Selective formation of the rctt chair stereoisomers of octa-O-alkyl resorcin[4]arenes using Bronsted acid catalysis. New Journal of Chemistry 2008, 32, 994-1002. (149) Gerkensmeier, T.; Mattay, J.; Naether, C.: A new type of calixarene: Octahydroxypyridine [4] arenes. Chemistry-A European Journal 2001, 7, 465- 474. (150) Morikawa, O.; Nagamatsu, Y.; Nishimura, A.; Kobayashi, K.; Konishi, H.: Scandium triflate-catalyzed cyclocondensation of 1, 3-dialkoxybenzenes with 1, 3, 5-trioxane. Formation of resorcin [4] arenes and confused resorcin [4] arenes. Tetrahedron letters 2006, 47, 3991-3994. (151) Barrett, A. G.; Braddock, D. C.; Henschke, J. P.; Walker, E. R.: Ytterbium (III) triflate-catalysed preparation of calix [4] resorcinarenes: Lewis assisted Brønsted acidity. Perkin Transactions 1 1999, 873-878. (152) Peterson, K. E.; Smith, R. C.; Mohan, R. S.: Bismuth compounds in organic synthesis. Synthesis of resorcinarenes using bismuth triflate. Tetrahedron Letters 2003, 44, 7723-7725. (153) Deleersnyder, K.; Mehdi, H.; Horváth, I. T.; Binnemans, K.; Parac-Vogt, T. N.: Lanthanide(III) nitrobenzenesulfonates and p-toluenesulfonate complexes of lanthanide(III), iron(III), and copper(II) as novel catalysts for the formation of calix[4]resorcinarene. Tetrahedron 2007, 63, 9063-9070. (154) Parac‐Vogt, T. N.; Deleersnyder, K.; Binnemans, K.: Lanthanide (III) tosylates as new acylation catalysts. European Journal of Organic Chemistry 2005, 2005, 1810-1815. (155) Hedidi, M.; Hamdi, S. M.; Mazari, T.; Boutemeur, B.; Rabia, C.; Chemat, F.; Hamdi, M.: Microwave-assisted synthesis of calix[4]resorcinarenes. Tetrahedron 2006, 62, 5652-5655. (156) Yan, C.; Chen, W.; Chen, J.; Jiang, T.; Yao, Y.: Microwave irradiation assisted synthesis, alkylation reaction, and configuration analysis of aryl pyrogallol[4]arenes. Tetrahedron 2007, 63, 9614-9620. (157) Carruthers, W.: Cycloaddition reactions in organic synthesis; Pergamon Press, New York, 1990. (158) Fringuelli, F.; Taticchi, A.: Dienes in the Diels-Alder reaction; Wiley New York, 1990. (159) Zincke, T.: Ueber die Einwirkung von Chlor auf o-Amidophenole und o-Diamine. Justus Liebigs Annalen der Chemie 1897, 296, 135-158. 121

Chapter 6 References (160) Zincke, T. H.; Pfaffendorf, W.: Über Tetrachlor-o-kresol und seine Umwandlung in Perchlorindon. Justus Liebigs Annalen der Chemie 1912, 394, 3-22. (161) v. Euler, H.; Josephson, K. O.: Über Kondensationen an Doppelbindungen. I.: Über die Kondensation von Isopren mit Benzochinon. Berichte der deutschen chemischen Gesellschaft (A and B Series) 1920, 53, 822-826. (162) Diels, O.; Alder, K.: Synthesen in der hydroaromatischen Reihe. Justus Liebigs Annalen der Chemie 1928, 460, 98-122. (163) Diels, O.; Alder, K.: Synthesen in der hydroaromatischen Reihe. III. Mitteilung: Synthese von Terpenen, Camphern, hydroaromatischen und heterocyclischen Systemen. Mitbearbeitet von den Herren Wolfgang Lübbert, Erich Naujoks, Franz Querberitz, Karl Röhl, Harro Segeberg. Justus Liebigs Annalen der Chemie 1929, 470, 62-103. (164) Berson, J. A.: Discoveries missed, discoveries made: creativity, influence, and fame in chemistry. Tetrahedron 1992, 48, 3-17. (165) Rogers, D. W.; McLafferty, F. J.: The influence of substituent groups on the resonance stabilization of benzene. An ab initio computational study. The Journal of Organic Chemistry 2001, 66, 1157-1162. (166) Carey, F. A.; Sundberg, R. J.: Advanced Organic Chemistry: Part A: Structure and Mechanisms; Springer, 2007. (167) Cossu, S.; Fabris, F.; De Lucchi, O.: Synthetic Equivalents of Cyclohexatriene in [4+2]-Cycloaddition Reactions: Methods for Preparing Cycloadducts to Benzene. Synlett 1997, 12, 1327-1334. (168) Cossu, S.; Battaggia, S.; De Lucchi, O.: Barrelene, a New Convenient Synthesis. The Journal of Organic Chemistry 1997, 62, 4162-4163. (169) Bickelhaupt, F.; de, W. W. H.: Unusual reactivity of highly strained cyclophanes. Journal of Physical Organic Chemistry 1998, 11, 362-376. (170) Chordia, M. D.; Smith, P. L.; Meiere, S. H.; Sabat, M.; Harman, W. D.: A Facile Diels−Alder Reaction with Benzene: Synthesis of the Bicyclo[2.2.2]octene Skeleton Promoted by Rhenium. Journal of the American Chemical Society 2001, 123, 10756-10757. (171) McCabe, J. R.; Eckert, C. A.: Role of high-pressure kinetics in studies of the transition states of Diels-Alder reactions. Accounts of Chemical Research 1974, 7, 251-257. (172) Chambers, R. D.; Edwards, A. R.: Cycloadditions and nucleophilic attack on Z- 2H-heptafluorobut-2-ene. Tetrahedron 1998, 54, 4949-4964. 122

Chapter 6 References (173) Matsumoto, K.; Sera, A.: Organic Synthesis under High Pressure; II. Synthesis 1985, 1985, 999-1027. (174) Dauben, W. G.; Bunce, R. A.: Organic reactions at high pressure. Asymmetric induction in the diels-alder reaction of p-benzoquinone with chiral 2, 4- pentadienoic acid derivatives. Tetrahedron Letters 1982, 23, 4875-4878. (175) Yates, P.; Eaton, P.: Acceleration of the Diels-Alder reaction by aluminum chloride. Journal of The American Chemical Society 1960, 82, 4436-4437. (176) Sauer, J.; Kredel, J.: Einfluss von lewis-säuren auf das endo-exo-verhaltnis bei diels-alder-additionen des cyclopentadiens. Tetrahedron Letters 1966, 7, 731-736. (177) Inukai, T.; Kojima, T.: Catalytic Actions of Aluminum Chloride on the Isoprene—Methyl Acrylate Diels-Alder Reaction. The Journal of Organic Chemistry 1966, 31, 1121-1123. (178) Walborsky, H.; Barash, L.; Davis, T.: Partial asymmetric synthesis in the diels- alder reaction. Tetrahedron 1963, 19, 2333-2351. (179) Tolbert, L. M.; Ali, M. B.: Transition states in catalyzed and uncatalyzed Diels- Alder reactions. Cooperativity as a probe of geometry. Journal of the American Chemical Society 1984, 106, 3806-3810. (180) Pindur, U.; Lutz, G.; Otto, C.: Acceleration and selectivity enhancement of Diels- Alder reactions by special and catalytic methods. Chemical Reviews 1993, 93, 741-761. (181) Houk, K. N.; Strozier, R. W.: Lewis acid catalysis of Diels-Alder reactions. Journal of the American Chemical Society 1973, 95, 4094-4096. (182) Diels, O.; Alder, K.: Synthesen in der hydroaromatischen Reihe. XII. Mitteilung. („Dien-Synthesen” sauerstoffhaltiger Heteroringe. 2. Dien-Synthesen des Furans.). Justus Liebigs Annalen der Chemie 1931, 490, 243-257. (183) Woodward, R. B.; Baer, H.: The Reaction of Furan with Maleic Anhydride1. Journal of the American Chemical Society 1948, 70, 1161-1166. (184) Eggelte, T.; De Koning, H.; Huisman, H.: Diels-Alder reaction of furan with some dienophiles. Tetrahedron 1973, 29, 2491-2493. (185) Hopff, H.; Rautenstrauch, C.: Addition products of butadiene with vinyl methyl ketone, maleic acid, etc. Patent, U. S., Ed.; US Patent 2262002, 1942. (186) Lane, L. C.; Parker, C. H. J.: Fumaric acid-conjugated hydrocarbon adducts. Patent, U. S., Ed.; US Patent 2444263, 1948. (187) Rideout, D. C.; Breslow, R.: Hydrophobic acceleration of Diels-Alder reactions. Journal of the American Chemical Society 1980, 102, 7816-17. 123

Chapter 6 References (188) Otto, S.; Blokzijl, W.; Engberts, J. B. F. N.: Diels-Alder Reactions in Water: Effects of Hydrophobicity and Hydrogen Bonding. The Journal of Organic Chemistry 1994, 59, 5372-5376. (189) Grieco, P. A.; Garner, P.; He, Z.-m.: “Micellar” catalysis in the aqueous intermolecular diels-alder reaction: rate acceleration and enhanced selectivity. Tetrahedron Letters 1983, 24, 1897-1900. (190) Gajewski, J. J.: A semitheoretical multiparameter approach to correlate solvent effects on reactions and equilibria. The Journal of Organic Chemistry 1992, 57, 5500-5506. (191) Assfeld, X.; Ruiz-López, M.; García, J.; Mayoral, J.; Salvatella, L.: Importance of electronic and nuclear polarization energy on diastereofacial selectivity of Diels– Alder reactions in aqueous solution. Chemical Communications 1995, 1371-1372. (192) Blokzijl, W.; Engberts, J. B. F. N.: Initial-state and transition-state effects on Diels-Alder reactions in water and mixed aqueous solvents. Journal of the American Chemical Society 1992, 114, 5440-2. (193) Otto, S.; Engberts, J. B.: Diels-Alder reactions in water. Pure and Applied Chemistry 2000, 72, 1365-1372. (194) Breslow, R.; Maitra, U.; Rideout, D.: Selective Diels-Alder reactions in aqueous solutions and suspensions. Tetrahedron Letters 1983, 24, 1901-4. (195) Breslow, R.; Maitra, U.: On the origin of product selectivity in aqueous Diels- Alder reactions. Tetrahedron Letters 1984, 25, 1239-1240. (196) Asano, T.; Le, N. W. J.: Activation and reaction volumes in solution. Chemical Reviews 1978, 78, 407-89. (197) Berson, J. A.; Hamlet, Z.; Mueller, W. A.: The correlation of solvent effects on the stereoselectivities of Diels-Alder reactions by means of linear free energy relationships. A new empirical measure of solvent polarity. Journal of the American Chemical Society 1962, 84, 297-304. (198) Cativiela, C.; García, J. I.; Mayoral, J. A.; Salvatella, L.: Solvent effects on endo/exo-and regio-selectivities of Diels–Alder reactions of carbonyl-containing dienophiles. Perkin Transactions 2 1994, 847-851. (199) Schlachter, I.; Mattay, J.; Suer, J.; Höweler, U.; Würthwein, G.; Würthwein, E.- U.: Combined quantum chemical and MM-approach to the endo/exo selectivity of diels-alder reactions in polar media. Tetrahedron 1997, 53, 119-132.

124

Chapter 6 References (200) Breslow, R.; Halfon, S.: Quantitative effects of antihydrophobic agents on binding constants and solubilities in water. In Proceedings of the National Academy of Sciences, USA, 1992; Vol. 89; pp 6916-6918. (201) Keay, B. A.: Intramolecular Diels–Alder reaction of the diene unit of furan in 2.0 M CaCl2. Chemical Communications 1987, 6, 419-421. (202) Blokzijl, W.; Blandamer, M. J.; Engberts, J. B. F. N.: Diels-Alder reactions in aqueous solutions. Enforced hydrophobic interactions between diene and dienophile. Journal of the American Chemical Society 1991, 113, 4241-6. (203) Otto, S.: Catalysis of Diels-Alder reactions in water. University of Groningen, 1998. (204) Breslow, R.; Zhu, Z.: Quantitative Antihydrophobic Effects as Probes for Transition State Structures. 2. Diels-Alder Reactions. Journal of the American Chemical Society 1995, 117, 9923-4. (205) Schneider, H. J.; Sangwan, N. K.: Changes of Stereoselectivity in Diels–Alder Reactions by Hydrophobic Solvent Effects and by β‐Cyclodextrin. Angewandte Chemie International Edition 1987, 26, 896-897. (206) Hirst, S. C.; Hamilton, A. D.: Complexation control of pericyclic reactions: supramolecular effects on the intramolecular Diels-Alder reaction. Journal of the American Chemical Society 1991, 113, 382-383. (207) Kang, J.; Rebek, J.: Acceleration of a Diels–Alder reaction by a self-assembled molecular capsule. Nature 1997, 385, 50-52. (208) Gouverneur, V.; Houk, K.; de Pascual-Teresa, B.; Beno, B.; Janda, K.; Lerner, R.: Control of the exo and endo pathways of the Diels-Alder reaction by antibody catalysis. Science 1993, 262, 204-208. (209) Siegel, J. B.; Zanghellini, A.; Lovick, H. M.; Kiss, G.; Lambert, A. R.; St.Clair, J. L.; Gallaher, J. L.; Hilvert, D.; Gelb, M. H.; Stoddard, B. L.; Houk, K. N.; Michael, F. E.; Baker, D.: Computational Design of an Enzyme Catalyst for a Stereoselective Bimolecular Diels-Alder Reaction. Science 2010, 329, 309-313. (210) Yoshizawa, M.; Tamura, M.; Fujita, M.: Diels-Alder in Aqueous Molecular Hosts: Unusual Regioselectivity and Efficient Catalysis. Science 2006, 312, 251- 254.

(211) Rose, K. N.; Hardie, M. J.; Atwood, J. L.; Raston, C. L.: Oxygen-center laden C2h symmetry resorcin[4]arenes. Journal of Supramolecular Chemistry 2001, 1, 35- 38.

125