A NEW LATE-STAGE LAWESSON’S CYCLIZATION STRATEGY TOWARDS THE SYNTHESIS OF ARYL 1,3,4-THIADIAZOLE-2-CARBOXYLATE ESTERS

A thesis submitted to the Kent State University Honors College in partial fulfillment of the requirements for Departmental Honors

by

Michael Joseph Schmidt

August, 2013

TABLE OF CONTENTS

LIST OF FIGURES...... v

LIST OF TABLES...... viii

ACKNOWLEDGEMENTS...... ix

CHAPTER

1. INTRODUCTION...... 1

1.1 Introduction to liquid crystals and their phases...... 1

1.1.1 Liquid crystal phases...... 2

1.1.2 Interaction of liquid crystals with electric fields and polarized light...... 5

1.2 Ferroelectric liquid crystals (FLCs) and their applications in liquid crystals displays (LCDs)...... 8

1.2.1 Molecular structure of ferroelectric liquid crystals...... 12

1.3 The synthesis of 1,3,4-thiadiazoles in liquid crystal materials...... 15

1.3.1 Ring-forming approaches to 1,3,4-thiadiazoles and other five-membered aromatic S-heterocycles...... 16

1.3.2 Ring-modifying approaches to 1,3,4-thiadiazoles and other five-membered aromatic S-heterocycles...... 25

1.4 Goals and scope of the current work...... 31

2. RESULTS AND EXPERIMENTAL DISCUSSION...... 33

2.1 Attempted application of alkyl 1,3,4-thiadiazole-2-carboxylate ester/thioester methodology to the preparation of aryl esters...... 33

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2.1.1 Introduction to previously established method for the synthesis of alkyl 1,3,4-thiadiazole-2-carboxylate esters and thioesters: complications from thiadiazole decarboxylation...... 33

2.1.2 Early studies towards the preparation of alkyl 1,3,4-thiadiazole-2- carboxylate esters...... 35

2.1.3 First use of sodium 1,3,4-thiadiazole-2-carboxylate salt...... 38

2.1.4 Preparation of the sodium 5-(4-octyloxyphenyl)-1,3,4-thiadiazole- 2-carboxylate salt (45)...... 42

2.1.5 Synthesis of 4-alkoxyphenols (63a-c)...... 45

2.1.6 Attempted preparation of aryl 1,3,4-thiadiazole-2-carboxylate esters 48 using previously developed esterification approach...... 46

2.2 Reevaluation of the synthesis of aryl 1,3,4-thiadiazole-2- carboxylate esters...... 51

2.2.1 Synthesis of 4-alkoxyphenyl oxalyl chlorides 67...... 52

2.2.2 Synthesis of 4-alkoxyphenyl (N’-(4-octyloxyphenylcarbonyl) hydrazinecarbonyl)formates 68a-c...... 54

2.2.3 Synthesis of 4-alkoxyphenyl 5-(4-octyloxyphenyl)-1,3,4- thiadiazole-2-carboxylates 48 via late-stage Lawesson’s cyclization...... 57

2.3 Liquid crystalline properties of 5-(4-octyloxyphenyl)-1,3,4- thiadiazole-2-carboxylate esters 48a-c...... 60

2.4 Potential future work...... 62

3. EXPERIMENTAL DETAILS...... 64

3.1 General considerations...... 64

3.2 Experimental details and schemes...... 65

REFERENCES...... 90

iv

LIST OF FIGURES

Figure 1.1: Schematic showing the N, SmA, and SmC phases...... 3

Figure 1.2: Schematic of the SmC* phase...... 5

Figure 1.3: Schematic of light polarization...... 7

Figure 1.4: Polarization/external field relationship for (a) paraelectic and (b) ferroelectric material...... 9

Figure 1.5: The off (a)/on (b) states of an SSFLC cell...... 10

Figure 1.6: The on (a)/off (b) states of a TN cell...... 11

Figure 1.7: General structure of ferroelectric materials. X = terminal dipolar groups, Y = central linkage, Z = chiral end group, L = lateral substituent, C = central core...... 13

Figure 1.8: Series of central and terminal links in Sm LCs...... 13

Figure 1.9: General structure of potential mesogen targets in the Seed/Sampson research group...... 14

Figure 1.10: The dipole and bend angles in some sulfur heterocycles...... 15

Figure 1.11: General cyclization approach to 5-membered S-heterocyclic aromatic compounds...... 16

Figure 1.12: Proposed cyclization mechanism of 1,4-dicarbonyl compounds to 1,3,4- thiadiazoles using Lawesson’s reagent (modified from Ozturk)...... 17

Figure 1.13: Parra’s complementary approaches to 2,5-diaryl-1,3,4-thiadiazole columnar LCs (reproduced from Parra)...... 19

Figure 1.14: Han’s use of Lawesson’s reagent for a study of 2,5-diaryl-1,3,4- thia/oxadiazole based liquid crystals (reproduced from Han)...... 20

Figure 1.15: A usefully divergent pathway to 1,3,4-Thiadiazoles and 1,2,4-Triazoles by Kurzer et al. (reproduced from Kurzer)...... 22

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Figure 1.16: Lebrini and coworkers’ use of microwaves in the synthesis of symmetrical 2,5-diaryl-1,3,4-thiadiazoles (reproduced from Lebrini)...... 23

Figure 1.17: Han’s use of microwaves in Lawesson’s cyclizations (reproduced from Han)...... 24

Figure 1.18: Rao’s use of sequential bromination/SNAr chemistry (reproduced from Rao)...... 26

Figure 1.19: Selective Sonogashira coupling approach by Lehmann and coworkers...... 27

Figure 1.20: Parra’s synthesis of some chiral Schiff-base containing 1,3,4-Thiadiazole- bassed liquid crystals (reproduced from Parra)...... 28

Figure 1.21: Lachances’s synthesis of 2-bromo-5-cyano-1,3,4-thiadiazole...... 29

Figure 1.22: Tanaka’s chemoselective thiazole synthesis...... 29

Figure 1.23: Methodology toward 1,3,4-thiadiazole-2-carboxylate esters previously established by our group which has not been extensively explored for aryl ester synthesis...... 31

Figure 1.24: General scheme of target molecules in this work...... 32

Figure 2.1: Several proposed pathways for thiadiazole decarboxylation (reproduced from Spinelli)...... 35

Figure 2.2: Bradley’s pathway to 2-hydro-1,3,4-thiadiazoles (reproduced from Bradley)...... 37

Figure 2.3: General strategy toward 1,3,4-thiadiazole-2-carboxylate esters first attempted by Bradley, later optimized by Sybo...... 39

Figure 2.4: Modifications by Wallace and Gans to Bradley/Sybo’s approach to 1,3,4- thiadiazole-2-carboxylate esters and thioesters...... 41

Figure 2.5: Reproduction of work by Bradley/Sybo, followed by attempted elaboration to aryl esters...... 42

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Figure 2.6: TLC analysis (10% EtOAc in petroleum ether) of the results of column chromatography of the ethyl ester (44)...... 44

Figure 2.7: Synthesis of 4-alkoxyphenols 63...... 46

Figure 2.8: Decarboxylated byproduct...... 48

Figure 2.9: Attempted use of phenoxide nucleophile 65a in the preparation of aryl 1,3,4- thiadiazole-2-carboxylate ester 48a...... 50

Figure 2.10 Reevaluation of synthesis of aryl 1,3,4-thiadiazole-2-carboxylate esters 48...... 52

Figure 2.11: Preparation of phenyl oxalyl chloride 66 (Liu) and the analogous aryl oxalyl chloride systems 67...... 53

Figure 2.12: The final three steps leading to target aryl 1,3,4-thiadiazole-2-carboxylate esters 48...... 54

Figure 2.13: TLC analysis of column chromatography of tricarbonyl intermediate 68a...... 56

Figure 2.14: Potential new directions for the late-stage Lawesson’s cyclization strategy...... 63

Figure 3.1: Synthesis of 4-alkoxyphenols...... 65

Figure 3.2: Synthesis of sodium 1,3,4-thiadiazole-2-carboxylate salt...... 71

Figure 3.3: Synthesis of final liquid crystal targets...... 79

vii

LIST OF TABLES

Table 2.1: Competition from decarboxylation side reaction during Sybo’s esterification reactions at various temperatures...... 40

Table 2.2: Summary of a periodically monitored esterification reaction targeting aryl 1,3,4-thiadiazole-2-carboxylate ester 48a...... 49

Table 2.3: Transition temperatures (in °C) of the target aryl 1,3,4-thiadiazole-2- carboxylate esters 48...... 60

Table 2.4: Transition temperatures (in °C) of the phenyl analog 69 of the target aryl 1,3,4- thiadiazole-2-carboxylate esters 48a and 48b...... 61

viii

ACKNOWLEDGMENTS

I would like to thank my family, first and foremost. Without their continued support, constant encouragement, and confidence in me, I would not have been able to accomplish half of what I have. I’d like to thank my sister, Carolyn Schmidt, for being a friend, confidante, cheerleader, partner in crime, and a generally awesome sibling. I’d like to thank my father Bill Schmidt for, among many other things, his financial and emotional support over the last 23 years, as well as being a great example to follow. I’d like to thank my mother Crystal Page for her support, love, and constant well-wishing.

I’d like to thank my grandparents Lucy and Ed Bailey for their very generous financial support throughout my undergraduate career, as well as being great examples of parents, friends, spouses, and hard workers. Finally, I’d like to dedicate this thesis to the memory of my grandmother, Sharon Schmidt. She was, without a doubt, the kindest, most generous, hardest working, and most loving person I’ve ever known. She also instilled in me a love of learning very early in life, teaching me to read before ever setting foot in a school. I doubt I would have pursued higher education without her influence.

I’d also like to thank the faculty members of the Kent State Univeristy

Department of Chemistry & Biochemistry that I have had the pleasure of working with and learning from over the past five years. I’d like to thank Drs. Paul Sampson and

Alexander Seed for the opportunity to perform research in their lab, and for their patience, advice, and encouragement. I’d especially like to thank them for their high

ix

expectations of me as a student—it has made me a better scientist. I’d like to thank Dr.

Robert J. Twieg for the opportunity to spend a summer working in his lab as part of an

REU experience. It was truly an excellent experience for me and my future career. I’d also like to thank my committee as a whole for taking time out of their undoubtedly busy schedules to participate in this process. It is much appreciated. I’d also like to thank all of the support staff around Williams Hall. Specifically, Erin Michael has been a gigantic help in generally allowing the chemistry department to run smoothly. I believe I speak for everyone when I give her a resounding “thank you.”

I’d also like to thank my fellow current and past members of the Seed/Sampson research group. To Dr. Alan Grubb, Pritha Subramanian, and Jonathan Tietz—thank you three for your mentorship, patience, and help in becoming proficient at bench work.

Without your help and guidance, the process would have been significantly more difficult. I’d also like to thank Emilie Hershberger-Kirk for being an excellent lab mate, and for her open-minded conversation about everything under the sun.

Finally, I’d like to thank all of my other fellow chemistry students and friends—

Randall and Michelle Breckon, Suvagata Tripathi, Sonya Adas, stockroom manager

Kristen Camputaro, Stephanie Ord, all of the other stockroom workers—your guys’ conversations, friendship, and shared cups of coffee have made the last five years go much better.

x 1

CHAPTER 1. INTRODUCTION

1.1 Introduction to liquid crystals and their phases

In addition to the three traditionally considered phases of matter, some materials are known to exhibit a fourth phase, known as the liquid crystal phase. This phase can be considered an intermediate phase somewhere between the disordered isotropic liquid phase and the more ordered solid phase. The most well-known and well-studied class of liquid crystals are thermotropic liquid crystals, which are pure substances whose phase behavior depends upon temperature.1 There exist other classes of liquid crystals, such as lyotropic liquid crystals, which are solutions of materials whose phase behavior depends upon both the temperature and concentration of the solution.1 These other classes will not be considered in this work.

To properly discuss liquid crystals, one must appropriately define their phases, and several different parameters are used to this end. First, it must be understood that the molecules within a liquid crystalline sample possess degrees of positional order (where do they lie in space?) and/or orientational order (in what direction do they lie in space, with respect to one another?) above that of an isotropic liquid and below that of a truly crystalline material.1 Some phases possess both orientational and positional order, while some lack positional order altogether. As a material warms from the solid state to a liquid crystal state, some (or all) of the positional order is lost, and as it warms further into the

2

isotropic liquid phase, any remaining positional and all orientational order is lost. The various liquid crystal phases differ in their degrees of positional/orientational order.1

1.1.1 Liquid crystal phases

The simplest (in terms of degree of order) liquid crystal phase is known as the nematic phase. It occurs when the molecules arrange themselves in such a way that they all orient (on average) in the same direction. This average direction, known as the director (n), is an important parameter used to define the order of various phases.1 While the molecules in this phase, on average, orient in one direction, they still move past one another in all three directions, in much the same way as the molecules in an isotropic liquid.

While achiral materials are known to exhibit the nematic phase, chiral materials are known to form a variation known, quite aptly, as the chiral nematic (N*) phase

(sometimes known as the cholesteric phase due to cholesteryl benzoate being one of the earliest known materials to exhibit this behavior).1 While in the normal nematic phase, the average molecular direction is the same throughout space (in both positive and negative directions), the director of the chiral nematic phase has an additional spatial dependence, rotating to form a twist through space. One way to view the chiral nematic phase is as layers of nematic material that are rotated with respect to one another. The molecular origin of this phenomenon is not hard to understand. In achiral nematic materials, the intermolecular interactions occur in such a way that the molecules lie

(again, on average) parallel to one another, whereas in the case of chiral nematic materials, the intermolecular interactions occur in such a way that the molecules orient

3

themselves at an angle to one another. The distance required for the director to make a full 360° rotation is known as the pitch (analogous to wavelength).1

Of the most common liquid crystal phases, the next most ordered phase is the smectic A phase. As in the nematic phase, the molecules orient, on average, in one direction, although the molecules in the smectic A phase tend to orient themselves in diffuse layers which are perpendicular to the director.1 Again, it should be emphasized that this order is an average, and the molecules are free to diffuse between layers. If the director lies along the z-axis, then the molecules freely diffuse in the xy-plane and occasionally move between layers in the z-direction. One point of view is to describe the smectic A phase as a layered nematic phase. Now, as opposed to the smectic A phase, the smectic C phase occurs when the molecules orient in an average given direction

(director) and in layers, but the director and the plane of the layers are no longer perpendicular to one another.1-2 In simple terms, this can be viewed as a “tilted” smectic

A phase. Figure 1.1 shows a schematic representation of the nematic (N), smectic A

(SmA), and smectic C (SmC) phases.

Figure 1.1: Schematic showing the N, SmA, and SmC phases

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Two primary physical theories have been put forth to describe the smectic C phase, those of McMillan3 and Wulf.4 McMillan’s theory, put forth in 1973, proposes that lateral dipoles in liquid crystal molecules are spinning around the long axis of the molecule in the smectic A phase, but molecules in the smectic C are far less prone to do so. As the molecules in the smectic A phase cool (and, thus, lose energy), their dipoles begin to align. As these dipoles “freeze out” and begin interacting, they produce torque which tilts the molecules, and this results in the tilt observed in the smectic C phase.3, 5

In contrast, Wulf’s theory (1975) posits that steric effects and the “zig-zag” shape of liquid crystalline molecules are instead responsible for this phase.4-5 Goodby2, 6 acknowledges that, while neither of these theories is fully sufficient, they both provide explanations for some of the observed behavior of the smectic C phase.

Liquid crystals exhibiting a chiral nematic phase may also exhibit a smectic A and/or smectic C phase,1-2 but the smectic C phase formed by chiral molecules is a modification known as the chiral smectic C phase (SmC*). In this phase, the layering and tilt of the smectic C phase are still in place, but the director precesses around an axis normal to the layer plane.1-2 Much like the chiral nematic phase, the chiral smectic C phase has a pitch, which is the distance required for the director to make a full rotation as it precesses. Figure 1.2 shows a schematic of the SmC* phase. Chiral smectic C materials have found numerous technological applications since their discovery including, but not limited to, optical switching/modulating devices,2 image scanners/printers,2 optical image and signal processing,2 and, of course, liquid crystal displays.2, 7 With the rapidly increased (and increasing) market share of LCD technology

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in mobile phone, computer, television, and digital camera displays,7 the advancement of associated materials is certainly of importance. While some academic research deals directly with these technological applications, much of it tends to focus on the preparation and analysis of new materials to fill the needed roles, as well as completely new areas of application for liquid crystalline materials.7 To fully understand the role played by liquid crystals in display and other optical applications, one must understand how these materials interact with light and how those interactions can be controlled via electric fields.

Figure 1.2: Schematic of the SmC* phase

1.1.2 Interaction of liquid crystals with electric fields and polarized light

It is well-known that charged objects interact, with like charges repelling one another and opposite charges attracting one another. The interaction produced by one

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charged object on all others is known as an electric field, and the interaction between liquid crystalline molecules and electric fields is of great importance for their optical applications. Much like charged objects, molecules with electric dipoles (that is, an uneven distribution of electron density within the molecule) also interact with electric fields.1

Consider a liquid crystal sample in the nematic phase, without an electric field present. The molecules have their longitudinal dipoles aligned along the director, equally in both the positive and negative directions, and their lateral dipoles are equally likely to orient themselves in any direction perpendicular to the director.1 Now, consider applying an electric field to the sample. The larger of the two dipoles (either longitudinal or lateral) will align with the electric field. In the case of the longitudinal dipole aligning, the director now sits aligned with the electric field, but in the case of the lateral dipole aligning, the director now sits aligned perpendicular to the electric field. In the case of materials in the SmC* phase, the helical twist of the director throughout layers is disrupted by the polarization caused by the electric field.5 In terms of application purposes, this means that one can control the alignment of molecules in a liquid crystal phase with the appropriate adjustment of an electric field, which will be discussed later.

Light is known to consist of both electric and magnetic field components that propagate in the same direction, but these components lie in planes perpendicular to one another. The polarization of light refers to the direction that the electric field component points in the xy-plane (given that the light is propagating in the z-direction). Normal, unpolarized light has components in all directions of the xy-plane, but by passing the

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light through a device known as a polarizer, the polarization can be adjusted. The most common type of polarization, linear polarization (or plane polarization), is obtained by only allowing light through that is polarized in a single direction.1-2 Figure 1.3 illustrates this concept well. Unpolarized light enters the first polarizer, letting through light which is linearly polarized in the vertical direction. As this light hits the second polarizer

(which is perpendicular to the first), no light is allowed through.

Figure 1.3: Schematic of light polarization

Chiral materials* are known to be optically active, and chiral liquid crystalline phases (such as the SmC*) show macroscopic form optical activity.2 This differs from the normal optical activity associated with chiral molecules, as the activity comes from the asymmetry of the bulk phase as a whole, not the individual molecules. When polarized light passes through a sample of material in the SmC* phase, the plane of polarization is rotated due to the helical nature of the phase. The helical nature of the phase is also responsible for the average electric polarization being zero ( = 0, not to

* When referencing “chiral materials”, it is intended to mean chiral non-racemic materials.

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be confused with the polarization of light), as the dipoles cancel each other out over a full rotation. This is termed helioelectric behavior. However, when an electric field is applied to a SmC* sample, the helical structure is unwound. Due to the helical structure being disrupted, and the asymmetry of the molecules, the electric polarization of the sample no longer averages to zero ( ≠ 0). This polarization tends to remain after removal of the electric field. Materials exhibiting this spontaneous polarization are termed ferroelectric, and are uniquely well-suited for many of the display applications mentioned above.

1.2 Ferroelectric liquid crystals (FLCs) and their applications in liquid crystal displays (LCDs)

Liquid crystals become polarized when an external electric field is applied, as previously described. In the case of normal nematic and smectic liquid crystals, when the electric field is removed, the polarization ceases (albeit, usually with some level of delay). In the case of ferroelectric liquid crystals (FLCs), the polarization of the sample persists after removal of the external field, leading to a hysteresis relationship between the polarization of the sample and the applied external electric field. This is illustrated well with a figure from Tietz,5 shown below.

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Figure 1.4: Polarization/external field relationship for (a) paraelectric and (b) ferroelectric materials5

The most common application of FLCs is that of SSFLCs (surface-stabilized ferroelectric liquid crystals). In SSFLCs, a ferroelectric liquid crystal material is sandwiched between two glass panes which have perpendicular light polarizers on either side of them (that is, light is linearly polarized before entering the cell and, depending upon the molecular orientation of the material, may or may not exit the other side).

When an electric field is applied in one direction normal to the glass panes, the cell does not rotate the plane of polarization of the light at all and the light does not pass through the cell. This is the “off” state. When an electric field is applied in the opposite direction

(still normal to the glass panes), the cell will twist the light by 90°, turning the cell to its

“on” state.1-2 Figure 1.5 shows schematics of both the “on” and “off” states of an SSFLC cell. Collings1 explains that for this phenomenon to occur, the cell gap must be shorter than the pitch length (typically 2 to 5 microns) to allow a substantial enough interaction between the LC and the surface. The angle between the director and the line perpendicular to the smectic layers (the tilt angle) should, ideally, be 22.5° (allowing a full 90° rotation of the incident light).

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Figure 1.5: The off (a)/on (b) states of an SSFLC cell8

The true appeal of SSFLC cells comes when they are compared to the more traditional twisted nematic (TN) cells (Figure 1.6). In a twisted nematic cell, the two glass panes are treated with an alignment agent and rubbed, causing an interaction between the LC material and the alignment agent in the direction of the rubbing. The directions of rubbing for the two panes are perpendicular to one another, causing a rotation of the material and the formation of a helical structure. Thus, no applied electric field leads to rotation of the incident light (due to the optical activity of the twisted structure). This allows light to pass through the second polarizer, and this leads to the

“on” state of the cell. However, applying an electric field unwinds the helical structure, and the cell no longer rotates light. This prevents light from passing through the second polarizer, which causes the cell to be in its “off” state.1 Thus, in the TN cells, a lack of

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electric field leads to the on state, and an applied electric field gives rise to the off state.

To go from the on state to the off state, one must apply an electric field. Removal of this field causes the material to relax back into its twisted (on) state. In the SSFLC cells, an applied electric field is responsible for both the on and off state, so the transition from

“on” to “off” is controlled by changing the direction of the applied electric field. Since the speed of an electric field aligning the molecules is so much quicker than the rate of relaxation for molecules without an applied field (elastic response), SSFLCs exhibit much quicker switching times than other LCDs. They are quicker by an order of one hundred to one thousand.1

Figure 1.6: The on (a)/off (b) states of a TN cell8

One other factor responsible for switching time in FLCs is the viscosity of the bulk material. Goodby2 explains that the switching time of FLCs has been suggested to be proportional to the applied torque, T, which is given by

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where η is the reorientational viscosity, Ps is the spontaneous electric polarization, and E is the magnitude of the applied electric field. Clearly, to decrease the applied torque, one can either increase the polarization or decrease the viscosity. Increasing the polarization can have detrimental effects, due to the fact that once a material is polarized, the strength of field required to reorient the material is increased. Thus, reduction of viscosity is generally seen as a superior approach. One method of viscosity reduction is to use a mixture of materials rather than a pure, chiral material. These mixtures typically consist of an achiral “host” material that is doped with strongly polarizable chiral materials. The reduction in viscosity is believed to be the result of less efficient packing of the molecules due to steric interactions at branched chiral centers.2

1.2.1 Molecular structure of ferroelectric liquid crystals

Thermotropic liquid crystals have a generally consistent structural motif, and several general trends regarding their structure/properties relationship have been deduced.

Goodby et al.9 determined a handful of general characteristics shared by most ferroelectric liquid crystal materials. These are generally materials containing (i) an alkyl-aryl-alkyl moiety, (ii) strong lateral dipoles, (iii) at least two aromatic rings in the aryl core, and (iv) a chiral center to reduce the symmetry of the phase (which induces the ferroelectricity).2, 9 Figure 1.7 schematically summarizes the various structural elements frequently encountered. The exact identities of the various elements (central/terminal linkages, central core, lateral substituents, etc.) can greatly impact the phase behavior of the bulk material. Aromatic central cores (C) promote smectic phase formation, and

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long (>7 carbon atoms) aliphatic tails tend to form tilted phases over orthogonal phases.

The central (Y) and terminal (X) linkage groups play a particularly important role in phase formation behavior. A series of both of these linkages and their tendency to form smectic phases (tilted phases, in particular) has been developed by Goodby, and is included in Figure 1.8.5 Strong lateral dipoles in the core also promote tilted phases.

Lateral substituents (L) can be used to impart these dipoles, but the increase in core width is known to reduce mesophase stability.

Figure 1.7: General structure of ferroelectric materials. X = terminal dipolar groups, Y = central linkage, Z = chiral end group, L = lateral substituent, C = central core

Figure 1.8: Series of central and terminal links in Sm LCs5

One long-term interest of the Seed/Sampson research group has been the preparation of mesogens of the general structure shown in Figure 1.9. Specifically, we are interested in the incorporation of sulfur-heterocycles in the Ar1 and Ar2 positions

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(which can be synthetically challenging), and the effects the various heterocycles have upon the properties of the final liquid crystalline targets. A range of thiophene, 3- and 4- fluorothiophene, and 1,3-thiazole systems have previously been investigated by our group, and the current work aims to investigate the previously unreported systems bearing a 1,3,4-thiadiazole ring at Ar2.

Figure 1.9: General structure of potential mesogen targets in the Seed/Sampson research group

Principles presented above form the basis of our rationale for targeting 1,3,4- thiadiazole-2-carboxylate esters as potential ferroelectric mesogens. The 1,3,4- thiadiazole moiety has a strong lateral dipole moment (3.0 D, shown in Figure 1.10) without the need for polar lateral substituents, such as fluorine. These substituents add width to the core of the molecule, and it is known that broadening of the core often leads to reduced mesophase stability. Thus, in comparison to analogous fluorinated systems

(4-fluoro-1,3-thiazole, for instance), the 1,3,4-thiadiazole systems will be narrower.

Fluorine in particular can be synthetically challenging to install—this area is another

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research focus of our group. The 1,3,4-thiadiazole unit also has a particularly small bend

(161.8 °) between the 2- and 5- carbons, and more linear motifs are known to promote smectic phase formation.1-2, 9 In addition, the 1,3,4-thiadiazole-based materials with ester linking groups are attractive due to both the tendency of the ester group to form smectic phases as well as its improved chemical stability over Schiff base linkages (a vital property for display applications, where materials need to be stable over a wide range of temperatures and other conditions over a long period of time). Seed10 presented a thorough overview of the various methods used in the literature to synthesize five- membered sulfur-containing heterocycles, as well as an appeal to their attractiveness in terms of property/structure relationships.

Figure 1.10: The dipole and bend angles in some sulfur heterocycles10

1.3 The synthesis of 1,3,4-thiadiazoles in liquid crystal materials

In general, synthetic approaches to 1,3,4-thiadiazoles can be classified in one of two ways: ring-forming or ring-modifying. Neither strategy is generally advantageous over the other; each target molecule should be evaluated on its own merits. The substituents on the 1,3,4-thiadiazole unit heavily influence the type of chemistry most well-suited to the material’s preparation.

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1.3.1 Ring-forming approaches to 1,3,4-thiadiazoles and other five-membered aromatic S-heterocycles

By far, the most common five-membered aromatic S-heterocycle ring-forming approach seen in the literature involves the cyclization of 1,4-dicarbonyl compounds using a thionating agent. With the appropriate bridging atoms (X, Y in Figure 1.11), one can easily obtain the thiophene, 1,3-thiazole, or 1,3,4-thiadiazole systems. Similar cyclization conditions are employed in all three systems, but the preparation of their corresponding 1,4-dicarbonyl precursors depends upon the nature of X and Y.

Figure 1.11: General cyclization approach to 5-membered S-heterocyclic aromatic compounds

Until Lawesson and coworkers performed their pioneering working in thionation chemistry,11-12 these cyclization reactions were typically carried out using phosphorus

13-14 pentasulfide (P4S10) at elevated temperature and extended reaction times. The eponymous Lawesson’s reagent (1)13 has proven more versatile and efficient than this method, and is now generally considered the standard reagent of choice in this cyclization approach. Lawesson’s reagent is commercially available, and is simply prepared by heating anisole and phosphorus pentasulfide for several hours, giving generally high yields (82% after 2 hours).14-15 The species itself is actually a non-reactive dimer that dissociates to its monomer (2) before reacting. Ozturk suggests that the first step in the

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ring-closure reactions of 1,4-dicarbonyl compounds is the thionation of both carbonyls,

13 which is followed by in situ cyclization and loss of H2S. Figure 1.12 shows this proposed mechanism for the 1,3,4-thiadiazole system, but the same general principle applies to the corresponding thiophene and 1,3-thiazole systems.

Figure 1.12: Proposed cyclization mechanism of 1,4-dicarbonyl compounds to 1,3,4- thiadiazoles using Lawesson’s reagent (modified from Ozturk13)

Parra et al.16 used the Lawesson’s cyclization as one of two ring forming approaches to some recently described 2,5-diaryl-1,3,4-thiadiazole-based columnar liquid crystals (see Figure 1.13). First, methyl 3,4-dihydroxybenzoate derivatives (3) were

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alkylated using standard Williamson etherification techniques (potassium carbonate,

DMF, 1-bromoalkanes), followed by a condensation reaction between the methyl ester and hydrazine to give the appropriate hydrazides (4). At this point, the material is diverged in two different routes. The first involves reacting the hydrazide with 4- nitrobenzoyl chloride to give the corresponding 1,4-dicarbonyl compound (5) to set up for a Lawesson’s cyclization, and these reactions proceed in good to excellent yield (70-

93%). Reduction of the nitro group using tin(II) chloride then gave the corresponding amine targets (6). In an alternative and complementary pathway, reaction of the hydrazide with ammonium isothiocyanate in the presence of hydrochloric acid gave the corresponding thiosemicarbazide (7). Dehydration using acetyl chloride followed by acidic hydrolysis gave the directly aminated 2-amino-1,3,4-thiadiazole species (8) in good yield (72-80%). The benefit of this approach by Parra is the complementary nature of the pathways, with the latter pathway giving the amino thiadiazole species, while the former approach gives the same species with a “phenyl spacer” between the thiadiazole and amino moieties. Another important strategic concept is illustrated by these pathways: the incorporation of ring-substitution prior to ring formation. As will be demonstrated later on, some transformations/substitutions of heterocycles are challenging

(or impossible) with the heterocycle portion already in place. One method to avoid these challenges is to postpone ring formation until the appropriate groups are already in place in the molecule, and this strategy will be demonstrated later on in this work.

19

Figure 1.13: Parra’s complementary approaches to 2,5-diaryl-1,3,4-thiadiazole columnar LCs (reproduced from Parra16)

20

Figure 1.14: Han’s use of Lawesson’s reagent for a study of 2,5-diaryl-1,3,4- thia/oxadiazole based liquid crystals (reproduced from Han17)

Han17 also made use of the Lawesson’s cyclization of 1,4-dicarbonyl compounds in a 2009 comparative study of 2,5-diaryl-1,3,4-thiadiazole/1,3,4-oxadiazole-based liquid crystals (see Figure 1.14). The target molecules (9a-c and 10a-c) all had four rings and a single long alkoxy chain. The central aim of the study was to systematically replace the internal two rings (thiadiazole/oxadiazole [9 and 10] in one position,

21

benzene/furan/thiophene [a, b, and c, respectively] in the other) and observe any differences in liquid crystalline phases. Reaction of the 4-alkoxybenzohydrazide with the appropriate p-bromoaroyl chlorides gave the 1,4-dicarbonyl compounds (12a-c). Each of these intermediates was subjected to treatment with either Lawesson’s reagent (to give the thiadiazoles 14a-c, 61-65%) or thionyl chloride (to dehydrate to the oxadiazoles 13a- c, 77-85%), giving a total of six advanced intermediates. Each of these was subjected to a Suzuki coupling with phenylboronic acid to give the final products (9a-c and 10a-c).

Kurzer18 and coworkers made use of an isothiocyanate to form 2-amino- substituted thiadiazoles. Ethoxycarbonyl isothiocyanate (15) was reacted with half an equivalent of hydrazine to give the (bis)thiourea (16) in 75-85% yield. Reaction with a full equivalent of hydrazine also gave the diadduct (with no evidence for the monoadduct), albeit in expectedly lower yields. While analogous to the 1,4-dicarbonyl compounds used in Lawesson’s/phosphorus pentasulfide-based approaches, the carbonyl groups are already thionated in this case, so cyclization is affected simply with ethanolic hydrochloric acid. This approach affords 2,5-dicarbamate-substituted thiadiazole (17) in

80% yield, a unique pair of substituents for these uncommon heterocycles.

One unique advantage of this pathway is the different divergent pathways available to the (bis)thiourea (16) intermediate. While acidic treatment gives the thiadiazole product of interest, refluxing in basic ethanol results in a different cyclization pathway to give the 3-amino-5-mercapto-1,2,4-triazole (18), while refluxing in hydrazine gave 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (19). The mechanism of the former reaction is believed to proceed to the final product via hydrolysis of intermediate 18a.

22

The authors propose a similar mechanism for the formation of 19, but they contend that evidence for alternative pathways is present, and as such, no definitive hypothesis was proposed.

Figure 1.15: A usefully divergent pathway to 1,3,4-Thiadiazoles and 1,2,4-Triazoles by Kurzer et al. (reproduced from Kurzer18)

23

Figure 1.16: Lebrini and coworkers’ use of microwaves in the synthesis of symmetrical 2,5-diaryl-1,3,4-thiadiazoles (reproduced from Lebrini19)

Several groups19-21 have demonstrated that microwave assisted methods may be extremely useful and efficient in ring-forming approaches to 2,5-diaryl-1,3,4- thiadiazoles. Lebrini19 and coworkers used microwave synthesis to generate a family (16 compounds) of symmetrical 2,5-diaryl-1,3,4-thiadiazoles (20) as potential corrosion inhibitors in acidic media. The appropriate aromatic aldehydes (21) were reacted with hydrazine monohydrate and elemental sulfur while under an elevated pressure of hydrogen sulfide (a very poisonous gas, making this method somewhat unattractive).

The rapid first step, formation of an azine intermediate, is followed by attack of hydrogen sulfide (formed in situ between hydrazine and the elemental sulfur) and cyclization to give the tetrahydro-1,3,4-thiadiazole, which is rapidly dehydrogenated by the sulfur.

Reaction times were short (~1 hour), especially compared to more traditional approaches

24

to these materials (~12 hours),19 and yields were high—the lowest yield obtained was that of the 2-thienyl adduct (75%).

In addition to work first established by our own group,22 Han et al.20 showed that microwave irradiated Lawesson’s cyclizations to afford 2,5-diaryl-1,3,4-thiadiazoles can be highly time and material efficient. 1,4-Dicarbonyl precursors (22) were prepared through previously described methods. Cyclization reactions using Lawesson’s reagent were performed under solvent-free conditions and generally took no longer than two to three minutes. The solid mixtures were irradiated in a household microwave oven until they turned entirely to a liquid, at which point the reactions were ceased to avoid any degradation, affording a series of 2,5-diaryl thiadiazoles (23) in good yield (80-91%).

The one major disadvantage of microwave approaches is the necessity of expensive equipment that, while becoming more popular, is not standard in most synthetic chemistry laboratories. Microwave reactions are also often difficult to scale up significantly, primarily due to local superheating within reaction vessels.

Figure 1.17: Han’s use of microwaves in Lawesson’s cyclizations (reproduced from Han20)

25

1.3.2 Ring-modifying approaches to 1,3,4-thiadiazoles and other five-membered aromatic S-heterocycles

In addition to methods which directly form the substituted 1,3,4-thiadiazole ring, there are also a significant number of approaches which modify a pre-existing 1,3,4- thiadiazole ring system. The 1,3,4-thiadiazole nucleus is notoriously electron-deficient which explains much of the reactivity of the system (rapid decarboxylation, facile displacement of halogens with nucleophiles, very little electrophilic aromatic substitution chemistry, etc.).23 This electron deficiency is explained by the electronegativity of the annular nitrogen atoms and resonance delocalization of the π-electrons.

Amino-substituted 1,3,4-thiadiazoles are popular reagents due to the effect of the electron-donating nature of the substituent. While standard electrophilic aromatic substitution reactions (nitration, sulfonation, halogenation, etc.) typically do not take place, 2-amino-1,3,4-thiadiazoles are known to react with bromine in acetic acid to effect

5-bromo substitution.23-24 Rao24 and coworkers used this reaction in a study of 2,5- diamino-substituted-1,3,4-thiadiazoles (24) as histamine H3 receptor agonists for the treatment of diabetes (see Figure 1.18). After brominating the 5-position of 2-amino-

1,3,4-thiadiazole (25) , the 2-position was also brominated using Sandmeyer-type chemistry. SNAr chemistry was then used to sequentially aminate the ring on either side in moderate yields (possibly due to formation of symmetrical diamino byproducts in the first reaction). Interestingly, 2-bromo-5-amino-1,3,4-thiadiazole (26) offers unique potential as a partner in selective coupling-type reactions (Heck, Suzuki, Stille, etc.).

One could easily imagine coupling the aromatic bromide, halogenating the amino-

26

substituted carbon through Sandmeyer-type chemistry, and then again coupling.

(Attempts to selectively couple the 2,5-dibromo compound (27) would also be worthwhile.) Such chemistry has not yet been explored.

Figure 1.18: Rao’s use of sequential bromination/SNAr chemistry (reproduced from Rao24)

Lehmann, Seltmann, and coworkers reported several25-27 studies of “V-shaped shape-persistent nematogens” of the general structure (28) shown in Figure 1.19. The approach utilizes another building block amenable to selective coupling reactions, 2-(4- iodophenyl)-5-(4-bromophenyl)-1,3,4-thiadiazole (29). The building block was first

25 26 made using P2S5 cyclization in poor yield, but the group later reported that use of

Lawesson’s reagent proved more efficient, as expected. By submitting the 1,3,4- thiadiazole 29 to normal Sonogashira conditions (in their case, piperidine, Pd(PPh3)4,

CuI, terminal alkyne) at room temperature, they were able to selectively couple at the C-I bond. Raising the temperature to 60 to 65 °C in a subsequent reaction (with similar or

27

identical conditions) allowed coupling at the C-Br bond. Figure 1.19 shows some of the various materials made by the group, with both symmetrical and unsymmetrical (thus necessitating the selective coupling approach) materials explored over several different studies. Interestingly, searches of both the Reaxys and SciFinder databases revealed no preparations of 2-bromo-5-iodo-1,3,4-thiadiazole (30), another building block which shows potential in the use of sequential, selective cross-coupling reactions. One early study28 showed the preparation of 2-bromo-5-fluoro-1,3,4-thiadiazole (31) (albeit, in only

16% yield), which could show potential in cross coupling/SNAr reaction sequences.

Figure 1.19: Selective Sonogashira coupling approach by Lehmann and coworkers25-27

28

Figure 1.20: Parra’s synthesis of some chiral Schiff-base containing 1,3,4- Thiadiazole-based liquid crystals (reproduced from Parra29)

Parra29 and coworkers used 2-amino-5-aryl-1,3,4-thiadiazoles (32) in the synthesis of some chiral liquid crystalline materials utilizing Schiff-base linkages in the core (see Figure 1.20). The aromatic amine was allowed to react with 4-formylphenol

(33) to give the Schiff-base, and this material was subsequently allowed to react with optically pure α-alkoxycarboxylic acids (34, utilizing the Steglich esterification) to give the target materials (36). The same method was used, albeit in a different order, to furnish materials (35) which possess the opposite connectivity of the terminal ester group. As previously mentioned, Schiff-base linkages in the core of liquid crystal materials are known to be some of the strongest at promoting tilted smectic phases. The downside, however, is that Schiff-bases are notoriously chemically unstable. Parra et al. found this to be true when attempting to study the ferroelectric properties of the materials

29

they made, as they decomposed before any meaningful measurements could be made.29

One common approach to circumventing this instability would be to utilize a linkage group with higher chemical stability, such as an ester. This is the basis for the work described in this thesis.

Figure 1.21: Lachances’s30 synthesis of 2-bromo-5-cyano-1,3,4-thiadiazole

Figure 1.22: Tanaka’s31 chemoselective 1,3-thiazole synthesis

In contrast to the plethora of methods outlined above for making various aryl-, halo-, and amino-substituted 1,3,4-thiadiazoles, methods for effectively forming 2- carboxy-1,3,4-thiadiazole moieties in the literature are extremely scarce. Most examples come from the patent literature, which is notoriously vague and inconsistent. One example of a nitrile-substituted 1,3,4-thiadiazole (37) was shown by Lachance,30 which can easily be envisioned as a masked carboxy unit. Recent32 advances in the Pinner reaction show potential for the elaboration of aromatic nitriles to the corresponding esters in the presence of alcohols. This type of chemistry could possibly be applied to our systems of interest, but no such work has been undertaken to date. Unfortunately, the experimental detail reported by Lachance was minimal, with the preparation of the nitrile

30

(2-bromo-5-cyano-1,3,4-thiadiazole, 37) being quoted from a patent without yield.

Tanaka31 and coworkers showed the preparation of the related ethyl 5-phenyl-1,3- thiazole-2-carboxylate (38) that involved the chemoselective cyclization of the 1,4- carbonyl groups in a 1,4,5-tricarbonyl precursor (39). Our group has utilized a similar strategy as a key step in our approach towards the synthesis of alkyl 1,3,4-thiadiazole-2- carboxylate esters33-35 (46) and thioesters36 (47) (see Figure 1.23). The approach includes the cyclization of the 1,3,4-thiadiazole moiety with the ethyl ester already installed at the

2-position, which is then submitted to basic hydrolysis to give the sodium carboxylate salt (45). While the 2-carboxylic acid moiety is known to readily decarboxylate,37-38 the sodium 2-carboxylate moiety has been shown to be bench stable in the solid state (in solution, however, decarboxylation is still an issue). Elaboration of this 2-carboxylate system to the corresponding highly electrophilic acid chloride is at the heart of our group’s strategy for making these challenging materials. This methodology (discussed in

Chapter 2) has come to fruition only after extensive work by Bradley35 and Sybo,33-34 with many of the attempted methods leading to decomposition of the thiadiazole unit or low yields. While this methodology has proven effective (albeit, demandingly so) for the preparation of alkyl esters and thioesters (46 and 47), it has not been extensively explored for the corresponding aryl esters (48). Prior to the work reported in this thesis, only a single example of an aryl 1,3,4-thiadiazole-2-carboxylate ester has been made (in moderate yield) via this method by our group.39

31

Figure 1.23: Methodology towards 1,3,4 thiadiazole-2-carboxylate esters previously established by our group which has not been extensively explored for aryl ester synthesis

1.4 Goals and scope of the current work

The present thesis research was focused on several goals. The first objective was to probe the effectiveness of our group’s previously developed 1,3,4-thiadiazole-2- carboxylate ester synthesis strategy for the formation of aryl 1,3,4-thiadiazole-2- carboxylate esters (48). Optimization of the existing process for these targets was anticipated. Ideally, this approach would be general enough to allow formation of a wide variety of carboxy-type substituents at the 2/5-position of a 1,3,4-thiadiazole ring, and with minimal experimental variation. The second goal, in the case the above method proved ineffective, was to develop an alternative entry point to these materials that was based on late-stage construction of the 1,3,4-thiadiazole ring. The third, and final goal,

32

was to generate a family of mesogenic aryl 1,3,4-thiadiazole-2-carboxylate ester-based materials to probe their utility as liquid crystalline materials for potential display purposes. These targeted materials have the general structure shown in Figure 1.24.

Specifically, we were interested in the tendency of these materials to form SmC phases.

The target materials possess many of the structural features previously established to be strong promoters of tilted smectic phases (strong lateral dipole, multiple aromatic rings within the core, ester internal linking group, ethereal outboard dipolar groups, nearly linear motif, and long aliphatic tails at either end). Therefore, we were optimistic that

SmC behavior would be exhibited by the targets.

Figure 1.24: General scheme of target molecules in this work.

33

CHAPTER 2. RESULTS AND EXPERIMENTAL DISCUSSION

2.1 Attempted application of alkyl 1,3,4-thiadiazole-2-carboxylate ester/thioester methodology to the preparation of aryl esters

2.1.1 Introduction to previously established method for the synthesis of alkyl 1,3,4-thiadiazole-2-carboxylate esters and thioesters: complications from thiadiazole decarboxylation

Many modern approaches for the formation of esters include the condensation between an alcohol and a carboxylic acid (or some functionalized derivative). Among the most common of these approaches are the classical acid-catalyzed Fischer esterification,40 the Steglich esterification,41-42 and the Mitsunobu reaction.43-45 While these methods have proven themselves to be robust, general, efficient, and applicable in complex syntheses, they rest upon the ability to form the carboxylic acid precursor. In the case of the 1,3,4-thiadiazole ring, the electron-deficient nature of the ring leads to rapid decarboxylation of both the carboxylic acid and the sodium salt of the carboxylic acid in solution. Spinelli37-38, 46 and coworkers have performed several studies on some of the effects affecting decarboxylation of 2-amino-1,3,4-thiadiazole-5-carboxylic acids, including proton activity and the role of substituents at the exocyclic nitrogen atom. The rate of decarboxylation increases as acidity increases, but below pH ~1, the rate begins decreasing again. The hypothesis that the facile nature of the decarboxylation is due to the electron-deficient nature of the ring is supported by the fact that the rate of decarboxylation dramatically increases when the 2-amino group is phenyl substituted.

34

The extra aromatic ring provides resonance structures which withdraw the electron density of the amine group away from the 1,3,4-thiadiazole unit, causing lower electron density in the ring and (as shown by Spinelli46), significantly slower decarboxylation.

Spinelli and coworkers38 proposed three possible mechanisms for decarboxylation of various nitrogen-containing heterocycles, including 1,3,4-thiadiazoles: one beginning with electrophilic aromatic substitution using a proton (Figure 2.1, Pathway I), one involving intramolecular proton transfer in concert with loss of carbon dioxide (Pathway

II), and the final pathway involving intramolecular proton transfer, followed by loss of carbon dioxide and a proton shift (Pathway III). For the amino-substituted systems,

Spinelli confidently showed that Pathway II does not occur, with Pathway III being the likely candidate for the actual mechanism (although a combination of Pathways I and III may be occurring).

35

Figure 2.1: Several proposed pathways for thiadiazole decarboxylation (reproduced from Spinelli38, 46)

2.1.2 Early studies towards the preparation of alkyl 1,3,4-thiadiazole-2- carboxylate esters

Problems associated with such decarboxylation reactions during 1,3,4-thiadiazole-

2-carboxylate ester synthesis were first encountered by Bradley, a former student in the

Seed/Sampson research group who attempted to tackle the problem of forming 1,3,4-

36

thiadiazole-2-carboxylate esters. Intending to use the free acid in standard synthetic transformations, various approaches to obtain the carboxylic acid 54 were attempted.

Most of these approaches involved initial formation of the 2-hydro-1,3,4-thiadidazole

(52) ring through Lawesson’s reagent-mediated cyclization of the bis-acylhydrazide (51), which was then to be elaborated to the acid (54). Various metalation techniques were tried, followed by trapping with ethyl chloroformate to give the ethyl thiadiazole ester

(56). Unfortunately, direct metalation using n-BuLi resulted in ring opening to give the corresponding nitrile (53) in 100% yield; however, borane complexation of the 3- thiadiazolyl nitrogen was found to be an effective solution to this problem. This method installs the carboxy moiety, albeit inefficiently, but further elaboration is required to obtain the various target esters.

37

Figure 2.2: Bradley’s pathway to 2-hydro-1,3,4-thiadiazoles (reproduced from Bradley35)

First targeting the longer chain alkyl esters, many different methods were attempted by Bradley,35 including coupling reactions of the free acid (54). The free acid was obtained by basic hydrolysis of the ethyl ester (56), followed by acidification with hydrochloric acid. The product acid (54) was obtained and characterized, but was found to be highly inefficient in its chemistry and to not be bench stable. Bradley performed a variable-temperature 1H NMR study of the acid, revealing that decarboxylation does not take place below -20 °C, while above 0 °C, the reaction became much more rapid. As a result, methods that proceeded via the free acid 54 were abandoned. Various transesterification protocols from ethyl ester 56 were also attempted, including those proceeding under acidic or basic catalysis, as well as reaction with a phenol in the

38

presence of molecular sieves to give the aromatic esters. Most esterification reactions resulted in either very poor efficiency or ring opening pathways leading to various byproducts (the aromatic nitrile 53, for instance, or to the protodecarboxylated species

52).

2.1.3 First use of sodium 1,3,4-thiadiazole-2-carboxylate salt

To open up efficient pathways to the various esters required for mesogenic studies

(primary and secondary alkyl esters and thioesters, aryl esters and thioesters), Bradley was the first to probe the effectiveness of using the sodium carboxylate salt 45 (easily accessible from the ethyl ester 44, and far more stable than the free acid 54) to form these different species (see Figure 2.3). Formation of the highly electrophilic acid chloride in situ from 45 followed by reaction with an alcohol was the first moderately successful approach to these thiadiazole esters, although Bradley had difficulty finding good conditions for the reaction. Early 1H NMR studies of the decarboxylation side reaction by Bradley showed that there was potential for these acid chloride-based esterification reactions to take place at low temperature (below -20 °C), but these studies were not probed further due to time constraints.

39

Figure 2.3: General strategy toward 1,3,4-thiadiazole-2-carboxylate esters first attempted by Bradley, later optimized by Sybo

Later work by Sybo33-34 eventually elaborated upon the work by Bradley to give an effective method for making alkyl 1,3,4-thiadiazole-2-carboxylate esters 46. While most of the work by Bradley was unchanged, the majority of Sybo’s work focused on fine tuning the very delicate conditions required for the esterification reactions. While a handful of minor changes were made to Bradley’s method (for instance, use of thionyl chloride rather than oxalyl chloride/cat. DMF to form the acid chloride), Sybo found the reaction temperature to be the biggest controlling factor for the esterification reaction. A very narrow range of reaction temperatures were required to achieve even moderately successful results, and these are summarized in Table 2.1.

40

Reaction Temperature Range % of Decarboxylated Byproduct 64

-4 to -7 °C 5-17%

-6 to -8 °C 0-4%

-10 to -17 °C > 20%

Table 2.1: Competition from decarboxylation side reaction during Sybo’s esterification reactions at various temperatures

It is believed that at the higher temperatures (~> -6 °C), the decarboxylation side reaction competes heavily with the formation of the desired esters 46. At the lower temperatures (~< -10 °C), it is believed that both reactions happen slowly, and upon workup/warming, the decarboxylation side reaction becomes dominant, leading to a high percentage of 2-hydrothiadiazole byproduct 64. The intermediate temperature range (-6 to -8 °C), combined with long reaction times, was found to be optimal. The butyl, hexyl, octyl, and decyl esters 46 were made via this method in 51-61% yield.

The first step of the current work was to evaluate this methodology for the preparation of aryl 1,3,4-thiadiazole esters. Several pieces of unpublished work by our group provided evidence that the method could be an effective one, albeit with the possible need of some slight modifications (see Figure 2.4). Work by Wallace36 showed improvements on Sybo’s method through the use of the corresponding alkoxides rather than the corresponding alcohols, improving the yield of the octyl ester (58) to 78%. This method also provided one example of the octyl thioester (57, 31% yield) and secondary cyclohexyl ester (59, 66%) in low to moderate yields respectively. It is possible that the low yield of the thioester is due primarily to the labile nature of the thioester functional

41

group, as thiols and thiolates are generally stronger nucleophiles than the corresponding alcohols and alkoxides. If nucleophilicity were the dominant factor in determining the course of the reaction, the thiols might be expected to be better substrates. Another piece of unpublished work by Gans39 actually provided a single example of the aryl esters targeted in this work, where a phenol nucleophile was employed to afford the corresponding phenyl ester 60 in moderate yield. However, only a single attempt was made and no studies optimizing the chemistry or establishing its reproducibility were performed.

Figure 2.4: Modifications by Wallace and Gans to Bradley/Sybo’s approach to 1,3,4- thiadiazole-2-carboxylate esters and thioesters

With the work of Bradley, Sybo, Wallace, and Gans in place, it was clear that there was potential for the use of this methodology in the formation of the targeted aryl esters. However, it was also clear that optimization of the process would be required for these sensitive systems. The first goal of the current work was to develop conditions that could effectively prepare the aryl esters. A secondary goal, should the first objective not be met (as was the case, to be discussed later), was to develop a pathway or method which circumvents the major issues with the previous method (inefficiency and

42

experimental difficulty, primarily) by exploiting a late-stage Lawesson’s cyclization reaction to directly construct the target aryl esters.

2.1.4 Preparation of the sodium 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2- carboxylate salt (45)

Figure 2.5: Reproduction of work by Bradley/Sybo, followed by attempted elaboration to aryl esters

The first step of the current work was preparation of the sodium 5-

(octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate salt (45) on a relatively large scale, as it was to be used in our studies repeatedly. First, methyl 4-hydroxybenzoate (40) was alkylated using standard Williamson etherification techniques (base, primary alkyl bromide, reflux) to give ether 41 in good yield (69%, ~30 g scale). The low melting point of the resulting product required a slightly modified recrystallization procedure. In a typical recrystallization procedure, the crude product is taken up into a minimum of

43

solvent which is at its boiling point (66 to 68 °C for the petroleum ether used in our laboratory). This is far above the melting point of methyl 4-octyloxybenzoate (35-36

°C),47 so to avoid oiling out the product, a slightly modified procedure was used. The material was taken up in solvent which had been warmed to ~30 °C (strictly kept below

35 °C) with a heat gun (a warm water bath is the preferred method, however, for safety reasons and for better control of the temperature). This solution was allowed to cool in an ice bath to crash the product out of solution, leading to moderate yield and good purity of the product 41. Reaction of 41 with a large excess of hydrazine monohydrate in refluxing ethanol gave 4-octyloxybenzohydrazide (42) in excellent yield (97%, ~44 g scale) with minimal purification.

4-Octyloxybenzohydrazide (42) was then allowed to react with ethyl oxalyl chloride in THF at room temperature in the presence of triethylamine (to mop up the HCl produced by the reaction). On both small and large scales (~ 1 g vs 10 g), the resulting tricarbonyl intermediate 43 was afforded in decent purity, although 1H NMR analysis showed trace impurities. However, these impurities proved non-detrimental to the following Lawesson’s cyclization as a whole, and so this product was used without further purification.

The ethyl tricarbonyl intermediate (43) was allowed to react with Lawesson’s reagent on a large scale (~7.5 g) with good results. Due to the sensitivity of the reaction to water, the crude, waxy starting material was scraped from its flask and dried in vacuo overnight to give a more brittle material that was far easier to work with. The reaction was performed in anhydrous THF at room temperature, and was found to be complete

44

after stirring for 24 hours under argon. Due to the large scale of the reaction, the crude material was split into two separate batches for purification by column chromatography.

The column ran in a highly reproducible manner. Non-polar impurities came off of the column first (fraction A), followed by fractions containing only product (fraction B). At some point, an impurity with somewhat lower polarity than the product began to elute simultaneously, but was present in such a small quantity that it had completely eluted before the product. While it was noted that these fractions (fractions C and D) were of lower purity, they also gave far less material than was obtained in fraction B (~2.7 g from

B, ~0.5 g from C and D combined). It appears that the majority of the product elutes before the impurities, and this important fact allowed effective preparation of the ethyl ester in large (4.86 g) quantity. The tendency of the product to form broad bands on the column and take extended periods of time to fully elute from the column may be caused by hydrogen-bonding-type interactions between the 1,3,4-thiadiazole nitrogens and the silanol groups on the silica gel.

Figure 2.6: TLC analysis (10% EtOAc in petroleum ether) of the results of column chromatography of the ethyl ester (44)

45

To obtain the sodium carboxylate salt 45, the ethyl ester 44 was submitted to basic hydrolysis using sodium hydroxide in EtOH and deionized water. Early attempts at the hydrolysis were unsuccessful using the exact amount of base as used by earlier researchers. This was suspected to be the result of fluctuations in the pH of the deionized water used. The method finally found to be effective involved simply adding solid base to the solvent until testing with pH paper read between 13 and 14. After stirring at room temperature for 48 hours, the white carboxylate salt was afforded in very good yield

(91%, 4.3 g scale). Interestingly, after sitting in an amber bottle under ambient atmosphere for 48 hours, the white powder was noted to have taken on a faint pink color.

1H NMR analysis of the pink material revealed no difference in purity. The origin of this color is unknown, but the phenomenon was noted during at least two separate preparations of the material on a gram-plus scale.

2.1.5 Synthesis of 4-alkoxyphenols (63a-c)

To form the target 4-alkoxyphenyl esters (48a-c), we required a series of 4- alkoxyphenols (63a-c). The synthesis of these materials was straightforward, and has been thoroughly described in the literature using a variety of conditions48-49 (see Figure

2.7). Commercially available 4-benzyloxyphenol (61) was alkylated using standard

Williamson etherification techniques (potassium carbonate, primary alkyl bromide, refluxing 2-butanone) and the product was recrystallized from petroleum ether. Diethers

62a and 62c were obtained in good (~85%) yields, whereas the decyl ether 62b was obtained in modest yield. The benzyloxy protecting group was then removed using hydrogen gas and catalytic palladium-on-carbon, using EtOH and EtOAc as cosolvents.

46

These reactions proceeded in somewhat variable (albeit acceptable) yield. It should be noted that the synthesis of these materials was not particularly concerned with efficiency, but was more focused on the purity of the resulting materials. Given the sensitive nature of the reaction in which they were to be used, yield was sometimes sacrificed for purity.

Figure 2.7: Synthesis of 4-alkoxyphenols 63

2.1.6 Attempted preparation of aryl 1,3,4-thiadiazole-2-carboxylate esters 48 using previously developed esterification approach

Following from the work of Gans, the aromatic esters (48a-c) were initially targeted via the acid chloride intermediate derived from carboxylate salt 45. The reactions were typically run as follows. First, a suspension of the carboxylate salt 45 in anhydrous toluene was sonicated under argon for 30 minutes before being cooled to between -6 and -8 °C. This temperature range was maintained at all times during the reaction, taking special care to maintain it during the addition of all reagents. This narrow range necessitated the use of a CryoCool-cooled cooling bath (acetone), as maintaining the temperature for long periods of time with a salt/ice bath was tedious and challenging. Thionyl chloride was then added to the mixture dropwise to form the acid chloride. The mixture was then stirred for approximately 90 minutes before diluting further with toluene. This was done for consistency with previous experiments by Sybo

47

and Bradley, who initially did so to facilitate stirring. The reaction was then allowed to stir for a further 60 minutes before adding anhydrous pyridine in a dropwise manner.

This served two purposes; one was to mop up any HCl produced during the reaction, and the second was to form a pyridinium acyl species which would be sufficiently electrophilic to form the aryl esters. The appropriate 4-alkoxyphenol had been separately dissolved in toluene at this point, and this solution was added to the flask dropwise. The reaction was then typically allowed to stir for extended periods of time (at least 20 hours) before aqueous workup.

The primary challenge of these reactions was suppressing formation of the byproduct 64 formed by decarboxylation. Crude reaction mixtures typically revealed product 48a:byproduct 64 ratios of between 1:1 and 1:3. Unsure of whether this byproduct was formed during the course of the reaction or upon workup, several experiments were performed and monitored at regular intervals over time. One example of these experiments is summarized below. At the 3 hour mark, three samples were removed and submitted to three different workup protocols to see if different results were obtained. Acidic workup consistently gave no product and large amounts of decarboxylated byproduct. While the relative amount of product as compared to byproducts generally increased over time, the increase was not significant, and the best ratio of product 48a to byproducts achieved in this experiment was 17% product 48a, 8% decarboxylation byproduct 64, and 76% starting phenol 63a (see sample G in Table 2.2).

Another similar experiment was run over a longer period of time (samples taken at 1, 20,

40, and 72 hours), and the best ratio of product to decarboxylated byproduct achieved

48

was 42% product 48a and 58% decarboxylation byproduct 64 at 40 hours. It was also clear from this experiment that, over long periods of time, the decarboxylation pathway dominates (at 72 hours, for instance, only 29% product 48a was observed compared to

71% byproduct 64).

Figure 2.8: Decarboxylated byproduct

49

Time Sample Temperaturea Workupb Productc Decarb.c Phenolc (Hours) A 1 -6 to -8 Normal 11% 8% 81% B 2 -6 to -8 Normal 9% 4% 87% 50% aq. AcOH, sat. C 3 -6 to -8 NaHCO3, water 100% 0.1 M HCl, sat. D 3 -6 to -8 NaHCO3, water 100% E 3 -6 to -8 Normal 10% 7% 83% F 5 -4 to -1 Normal 9% 6% 84% G 7 2 to 3 Normal 17% 8% 76% H Warmed Overnight Normal 13% 7% 80% a This is the temperature at which the reaction mixture was maintained between the current and previous sample taken. b Normal workup refers to washing with sat. c NaHCO3 and then washing with water. These are the relative values given by integration of proton NMR signals for the corresponding compound. The values are normalized to “per proton” integrations.

Table 2.2: Summary of a periodically monitored esterification reaction targeting aryl 1,3,4-thiadiazole-2-carboxylate ester 48a

It was postulated at this point that, in order to effectively form the target material,

the reaction leading to the aryl ester 48 would need to be faster than the decarboxylation

side reaction leading to unwanted byproduct 64. One possible reason for the sluggish

nature of the desired esterification reaction is the less nucleophilic nature of phenols as

compared to alcohols. To circumvent this, we attempted to use the preformed

deprotonated phenoxide 65a in lieu of the phenol 63a. Two separate attempts were made

using this approach, one using sodium metal to deprotonate the phenol and one using

NaH. The reaction using sodium metal to form the phenoxide 65a led to a very poor ratio

of product to decarboxylated byproduct (<1:10). The reaction using sodium hydride

(60% dispersion in mineral oil) led to a slightly better ratio (~1:7), but was still deemed

to be too inefficient to be worth pursuing further.

50

Figure 2.9: Attempted use of phenoxide nucleophile 65a in the preparation of aryl 1,3,4-thiadiazole-2-carboxylate ester 48a

Despite the poor efficiency of these reactions, attempts to purify the small amount of aryl ester product 48a formed were made using column chromatography. Previous members of our group who worked with 1,3,4-thiadiazole systems found it necessary to pretreat the silica gel with base (10% triethylamine in petroleum ether) before using it to purify their materials by column chromatography. Expecting that our aryl ester product

48a would probably suffer from the same drawback, the same pretreatment was used in all attempts to chromatograph the crude product mixtures of these reactions. As was discovered during later studies (see Section 2.2.3), the base pretreatment ultimately proved to be detrimental to the purification of these aryl 1,3,4-thiadiazole esters, giving only the previously described 2-hydro-1,3,4-thiadiazole byproduct 64 after chromatography. Thus, the small amount of desired aryl ester product 48a had apparently decomposed during chromatography. No attempts were made to purify the product from these reactions without base pretreatment of the silica gel, as a superior approach was uncovered (see below).

51

2.2 Reevaluation of the synthesis of aryl 1,3,4-thiadiazole-2-carboxylate esters

Due to the difficulties faced using the previously established method, a new pathway for the synthesis of aryl 1,3,4-thiadiazole-2-carboxylate esters 48 was deemed necessary. The difficulties in applying the previously established method stemmed from the sensitivity of the 2-carboxy-1,3,4-thiadiazole moiety to decarboxylation. It was postulated that if formation of the sensitive aryl 1,3,4-thiadiazole-2-carboxylate ester unit was postponed until the end of the synthesis, the process would most likely be far more efficient. Ideally, the crucial C-O bond formation would take place before the formation of the 1,3,4-thiadiazole unit. The reaction of benzohydrazides with acid chlorides has already been shown to be an effective method for formation of 1,4,5-tricarbonyl compounds such as 43, which serve as suitable precursors for Lawesson’s cyclization. In the new pathway, instead of the ethyl group being already in place from the commercially available ethyl oxalyl chloride, we would be required to design a pathway to form 4- alkoxyphenyl oxalyl chlorides. Figure 2.10 visually summarizes the new pathway postulated in the current work.

52

Figure 2.10 Reevaluation of synthesis of aryl 1,3,4-thiadiazole-2-carboxylate esters 48

2.2.1 Synthesis of 4-alkoxyphenyl oxalyl chlorides 67

The synthesis of aryl oxalyl chlorides has been reported,50-51 but the methods vary from one another. Liu50 reported a simple method utilizing the inexpensive and readily available oxalyl chloride (see Figure 2.11). After attempting a method previously reported by another group,51 Liu and coworkers found that refluxing phenol in a large excess of oxalyl chloride effectively gave phenyl oxalyl chloride 66, although, of some concern was that they did not report a chemical yield for the process (the paper was concerned with the medicinal properties of the target materials). In our laboratory, the 4- alkoxyphenol was simply added to a large excess of oxalyl chloride and allowed to reflux overnight under argon. Excess oxalyl chloride was removed in vacuo (via rotary

53

evaporator, which should be thoroughly and carefully cleaned afterwards with EtOH to avoid degradation of the vacuum seals). To ensure full removal of the excess oxalyl chloride, which would certainly interfere with the next step, the crude acyl chloride was diluted with anhydrous toluene which was also removed in vacuo. It is unknown whether the toluene and oxalyl chloride form an azeotrope or if the evaporation of the toluene simply ensures complete removal of the oxalyl chloride (which boils more than 40 °C below toluene), but the method has proven effective for the complete removal of oxalyl chloride. It should also be noted that every effort to keep moisture out of the system was made. Whenever the flasks containing the acyl chlorides 67 were not actively being moved between the fume hood and the rotary evaporator, they were fitted with either an argon bubbler or with a septum with an argon inlet needle and a vent needle.

Figure 2.11: Preparation of phenyl oxalyl chloride 66 (Liu50) and the analogous aryl oxalyl chloride systems 67

54

Figure 2.12: The final three steps leading to target aryl 1,3,4-thiadiazole-2- carboxylate esters 48

2.2.2 Synthesis of 4-alkoxyphenyl (N’-(4-octyloxyphenylcarbonyl) hydrazinecarbonyl)formates 68a-c

The crude acyl chlorides 67 were subsequently allowed to react with 4- octyloxybenzohydrazide 42 to form the key 1,4,5-tricarbonyl intermediates 68. These reactions were performed at room temperature in anhydrous THF. Solutions of both the benzohydrazide 42 and the acyl chloride 67 were prepared. 1.5 Equivalents of anhydrous triethylamine were added in a single portion to the benzohydrazide solution. The base serves the role of mopping up the HCl produced by the reaction of the nucleophile with the acyl chloride.

Previous attempts by Bradley and Sybo to purify the tricarbonyl intermediates in their projects proved challenging, as did the purification of these materials (68 in Figure

2.12). Due to the highly polar nature of the material, a silica plug was deemed a likely candidate for purification. First, an eluent was found which moved the byproducts on

55

silica gel but left the product at the baseline (30% EtOAc in petroleum ether), and then an eluent was found which moved the very polar product (2 to 5% MeOH in CH2Cl2). The polar elution gave a material that was primarily product but which was not pure by 1H

NMR analysis (approximately 8:1 ratio of product 68a to phenol byproduct 63a).

Recrystallization of this material from EtOH gave pure product 68a as a light tan powder, albeit in low yield (10%).

Considering that the poor separation using the silica plug might be circumvented by using formal column chromatography, the next purification attempts utilized column chromatography. Again, the highly polar nature of the materials demanded a highly polar eluent system. Due to the large difference in polarity of the materials in question, gradient elution was deemed necessary. The intended procedure was to wash off all of the less polar byproducts (phenols 63, for instance) with a (relatively) non-polar eluent, and then retrieve the product from the column with a highly polar eluent. The procedure and results are summarized by the TLC plate shown in Figure 2.13. Fraction A (30%

EtOAc/petroleum ether) gave primarily phenol 63a, with other trace impurities (>10%).

Fractions B and C (30% EtOAc/petroleum ether to 40% EtOAc/petroleum ether to 2%

MeOH/CH2Cl2) both contained product 68a with 43% and <10% phenol 63a, respectively.

56

Figure 2.13: TLC analysis of column chromatography of tricarbonyl intermediate 68a

An attempt was made to separate the phenol out from fraction B by washing with aqueous base (5% KOH), but this led to complete decomposition of the product. Due to the poor recovery and inefficiency of the purification, attempts were made to purify the crude reaction product by recrystallization. Recrystallization using any nucleophilic solvent (EtOH, water) resulted in decomposition of the material (in the case of EtOH, it led to transesterification to the ethyl tricarbonyl ester 43 which was confirmed by 1H

NMR analysis). Recrystallization was attempted using EtOAc, EtOAc/petroleuem ether

(25% EtOAc, 50% EtOAc, 75% EtOAc), DME, DME/H2O (decomposition), diethyl ether, and dichloromethane. In all cases, the material was simply too insoluble to effectively recrystallize. Seeing this as a possible benefit, several attempts were made to simply wash the soluble impurities away from the highly insoluble product using diethyl ether. The material was stirred in ether at room temperature, and the solvent was decanted. Repeating this process several times afforded product 68a with good purity, but the recovery was equally poor (≥20%) to those recoveries seen during similar attempts to purify by chromatography. These difficulties led to the conclusion that the

57

most efficient course of action was direct use of the crude material 68 in the next step without purification.

2.2.3 Synthesis of 4-alkoxyphenyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2- carboxylates 48 via late-stage Lawesson’s cyclization

After previous workers showed that the crude 1,4,5-tricarbonyl intermediate 43 could effectively be cyclized to give the ethyl ester 44, it was postulated that the same outcome should be possible for the corresponding aryl esters 48. While much of the literature utilizing Lawesson’s reagent does so in refluxing toluene, our group has found success in using Lawesson’s reagent in THF at room temperature. The room temperature reactions of crude tricarbonyl intermediate 68a in THF necessitated the use of extended reaction times (24 to 72 hours) and an excess of Lawesson’s reagent 1 (1.2 equivalents, which corresponds to 2.4 equivalents of “thionating agent” 2 due to the dimeric nature of

Lawesson’s reagent) to completely consume the starting material. However, it was found that when the reaction of tricarbonyl intermediate 68a was run in refluxing toluene, the starting material was completely consumed after much shorter times (2 to 4 hours) and with less Lawesson’s reagent (0.6 equivalents). This contradicts the mechanism proposed by Ozturk13 in Figure 1.12, which presupposes the need for a full equivalent of

Lawesson’s reagent. The reactions also seemed to produce a cleaner product, most likely due to less competition from side reactions at shorter reaction times. Of most importance, no significant amounts of phenols 63 were observed in the crude product mixtures.

Purification of the final products from these Lawesson’s reagent-mediated cyclization reactions proved somewhat challenging. In previous work by our group,

58

including the preparation of the alkyl 1,3,4-thiadiazole-2-carboxylate esters 46, the silica gel used in chromatography required pretreatment with triethylamine for successful separation. In the absence of this pretreatment, it was postulated that the acidic sites on the silica gel were catalyzing a decarboxylation reaction leading to the 2-hydro-1,3,4- thiadiazole byproduct 64. Such a pretreatment also presumably interrupted any hydrogen bonding interactions between the 1,3,4-thiadiazole ring-nitrogen atoms and the silica gel, leading to better separation. As a result, it was assumed we would need to follow this same protocol for the aryl ester targets 48, especially given their more labile nature compared with the corresponding alkyl esters 46 (see earlier). Suprisingly, the exact opposite outcome was observed. Early experiments involving the purification of 48a by column chromatography with Et3N pretreatment gave very poor results, with poor separation and evidence of decarboxylation of the product during purification.

To probe the effect of column base pretreatment on the purification of these aryl ester materials, two separate experiments were performed in which, in each case, the crude aryl ester product 48 was prepared and split into two equal-sized portions. One portion was chromatographed with base pretreatment of the silica gel, and the other portion was chromatographed without such pretreatment. In both cases, the base pretreated columns gave no fractions of pure product 48a, affording only fractions containing significant quantities of decarboxylated byproduct 64 (~1:1 mixture with the desired aryl ester targets), and fractions of the phenolic starting material. Also in both cases, the column without pretreatment gave the intended product in moderate to good

(59 to 65%) recovery and good purity. Only small traces of the starting phenol were

59

observed by 1H NMR analysis in most cases. In one case (the 4-decyloxyphenyl ester

48b), a significant portion of the phenol did contaminate the fractions containing the desired aryl ester product (1:0.5 product 48b:phenol 63b). In this case, the phenol was also present in a similar ratio in the crude starting material. There is no evidence to suggest that decomposition took place on the column itself. After chromatography, targets 48a and 48c were obtained in good yield (65% and 59% over three steps, respectively) and good purity, but target 48b was contaminated significantly with phenol byproduct 63b.

Further purification was performed to obtain products of very high purity

(required for mesogenic studies and LC applications). Recrystallization (using DME) of the products obtained from the column without pretreatment gave the target materials 48 in high purity and moderate overall yield (21 to 35% for three steps, starting from the 4- alkoxyphenols 63).

This new approach to the synthesis of aryl 1,3,4-thiadiazole-2-carboxylate esters

48 represents an alternative to the synthetically demanding protocol that had previously been developed by our group for the analogous alkyl esters and thioesters. Comparisons of direct yields for the two methods are difficult to make. Only a single example of an aryl 1,3,4-thiadiazole-2-carboxylate ester has been reported by our group (60) using the previous method, and this chemistry was found to be highly irreproducible in attempts conducted during the course of the current thesis research. Beginning from commercially available methyl 4-octyloxybenzoate (40), the target materials 48 were prepared in 14 to

23% overall yield over 5 steps using the late-stage ring building approach. The greatest

60

benefit of the new method lies in its reproducibility and experimental ease. It avoids the experimentally demanding (and inconsistent in the case of aryl esters) esterification reaction that was central to the previously developed approach for alkyl 1,3,4-thiadiazole-

2-carboxylate ester synthesis, where the use of extended reaction times, narrow and sensitive temperature ranges, and very small reaction scales are all unattractive and are impractical for multi-gram synthesis.

2.3 Liquid crystalline properties of 5-(4-octyloxyphenyl-1,3,4-thiadiazole-2- carboxylate esters 48a-c

n Cryst I Cryst II SmC N Iso. Liq. Recryst. 8 ▪ 100.7 ▪ 105.1 ▪ 175.4 ▪ 187.8 ▪ 85.2 10 ▪ 100.1 -- -- ▪ 175.3 ▪ 183.5 ▪ 84.9 12 ▪ 98.9 -- -- ▪ 174.3 ▪ 180.1 ▪ 84.4

Table 2.3: Transition temperatures (in °C) of the target aryl 1,3,4-thiadiazole-2- carboxylate esters 48. The symbol “▪” implies the existence of the corresponding phase, while the symbol “--“ implies the lack of the corresponding phase. Temperatures were obtained through the use of polarizing optical microscopy and differential scanning calorimetry (DSC).

Table 2.3 summarizes the transition temperatures and phase behavior of the target esters 48. As anticipated, the materials exhibit wide SmC phases (70.3 to 75.4 °C wide ranges). This result supports the hypothesis that the analogous chiral esters will likely exhibit ferroelectric behavior. The high melting points of the materials could be a hurdle

61

in display properties, but carefully targeted structural modifications would be expected to lower these temperatures. Table 2.4 (data from Goodby52) shows the transition temperatures of the analogous systems 69 in which the 1,3,4-thiadiazole rings of 48a and

48b are replaced with a p-substituted phenyl ring. One very clear improvement upon the phenyl systems is the range of the SmC phase observed. In 69, the widest range (n = 8,

49°C) is 21 °C narrower than the narrowest range for structures 48 (48a, n = 8, 70.3 °C).

The melting point of the aryl 1,3,4-thiadiazole-2-carboxylate esters are also noticeably

(~10 °C) lower than their phenyl analogues. While still not ideal, this result represents a step towards materials which meet the necessary requirements, while also showing potential as host materials in these applications. In addition, the phenyl-based systems display a higher-ordered smectic phase (SmB) below the SmC phase and this can be problematic when formulating mixtures as injected smectic phases can result. This phase is absent in the corresponding 1,3,4-thiadiazoles 48.

n Cryst SmB SmC SmA Iso. Liq. Recryst. 8 ▪ 110 ▪ 116 ▪ 165 ▪ 200 ▪ 71 10 ▪ 107 ▪ 116 ▪ 162 ▪ 194 ▪ 64

Table 2.4: Transition temperatures (in °C) of the phenyl analog 69 of the target aryl 1,3,4-thiadiazole-2-carboxylate esters 48a and 48b (data for 69 with n=12 was unavailable). Data from Goodby.52

The one advantage that is offered by the phenyl-based systems is that these materials display a smectic A phase which aids in alignment when constructing devices.

62

Overall, however, the 1,3,4-thiadiazole systems synthesized in this project show great promise and offer several advantages over the analogous phenyl-based systems.

2.4 Potential Future Work

In terms of new materials, the most obvious extension of the current work is in the preparation of chiral ester derivatives of the materials for evaluation of their potential ferroelectric properties. While the current materials show potential as host materials, their symmetry does not allow for ferroelectric behavior. This new late-stage ring building chemistry could also be applied toward the synthesis of aryl esters containing related heterocyclic cores, such as thiophenes and 1,3-thiazoles.

Due to the experimentally challenging and demanding nature of the previous method for 1,3,4-thiadiazole-2-carboxylate ester synthesis, application of this new approach in the synthesis of alkyl esters and thioesters may also prove more efficient than our previously developed approaches. Such studies would also provide a more direct comparison of the two methods, allowing a fuller exploration of the pros and cons of both methods. The new method could also prove effective in making materials with different linking groups within the molecule, such as ethers 70 in Figure 2.14.

One area where the new method needs further development is in the formation of the aryl oxalyl chloride species 67. The crude 1H NMR spectrum of the tricarbonyl intermediates 68 frequently showed starting phenol, and it is unclear if this phenol was present in the starting aryl oxalyl chloride, or if it is a byproduct of one of the subsequent

63

reactions. No attempts have yet been made to isolate or purify the aryl oxalyl chlorides, and perhaps doing so would be beneficial to the overall synthesis.

Figure 2.14: Potential new directions for the late-stage Lawesson’s cyclization strategy

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CHAPTER 3. EXPERIMENTAL DETAILS

3.1 General considerations

Unless otherwise noted, all chemicals were used as received from the supplier

(Sigma-Aldrich, Acros Organics, TCI America, and/or Alfa Aesar). All structure elucidation was performed using 1H NMR (400 MHz, Bruker Avance 400 MHz spectrometer running Topspin version 2.1 software with TMS as internal standard) and

13C NMR (100 MHz) spectroscopy. Reactions were monitored using TLC (aluminum- backed silica gel plates, Sigma-Aldrich, 200 μm layer thickness, 2-25 μm particle size and 60 Å pore size) or previously described NMR techniques. Column chromatography was typically performed under positive air pressure (flash column chromatography) using

Fisher Scientific silica gel (Davisil™,170-400 Mesh, Type 60A, Grade 1740). Anhydrous tetrahydrofuran and toluene were distilled from Na metal/benzophenone, anhydrous triethylamine and pyridine were distilled from CaH2, and all other solvents/reagents not used as received were purified as noted. All anhydrous solvents were distilled under argon. When glassware is said to be “oven-dried argon-cooled”, the glass was thoroughly washed, rinsed with acetone, dried in an oven overnight (approx. 150° C), and cooled to room temperature under an argon bubbler before use. Petroleum ether (bp 66 to

68 °C) and ethyl acetate used in column chromatography were distilled prior to use.

Optical microscopy was performed using a Leitz Laborlux 12 Pol S microscope, with a

Mettler Toledo FP82HT Hot Stage used in conjunction with a Mettler Toledo FP90

65

Control Processor. DSC analysis was performed using a TA Instruments Differential

Photocalorimeter (DSC2920 Modulated DSC).

3.2 Experimental details and schemes

Figure 3.1: Synthesis of 4-alkoxyphenols

1-Benzyloxy-4-octyloxybenzene (62a)

4-Benzyloxyphenol (10.04 g, 50.14 mmol), 1-bromooctane (14.66 g, 75.91 mmol), and potassium carbonate (14.02 g, 101.4 mmol) were all placed in a 500 mL pear-shaped flask with 2-butanone (200 mL). The mixture was brought to reflux and stirred overnight. The next day, the mixture was cooled briefly before filtering off the potassium salts and washing the filtered solid with acetone (100 mL). The filtrate was washed with aqueous NaOH (1 M, 2x100 mL) and deionized water (2x100 mL), and dried over MgSO4. The solution was filtered, and the solvent was removed in vacuo.

The crude product was then recrystallized from petroleum ether (taken up in a minimum of petroleum ether which had been warmed to 55 °C and cooled in an ice-water bath),

66

yielding 13.85 g (88% yield) of white crystals. mp = 69.8-70.7°C (lit.53 68-69 °C). 1H

NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 6.8 Hz), 1.23-1.40 (m, 8H), 1.44 (quint, 2H,

J = 6.9 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 3.89 (t, 2H, J = 6.6 Hz), 5.01 (s, 2H), 6.82 (d,

2H, J = 8.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 7.28-7.45 (m, 5H). 13C NMR (100 MHz,

CDCl3): δ 153.54, 152.85, 137.36, 128.56, 127.50, 115.81, 115.40, 70.71, 68.64, 31.84,

29.41, 29.27, 26.09, 22.69, 14.13. [Note: Two carbon signals are believed to be missing due to aliphatic overlap.]

4-Octyloxyphenol (63a)

1-Benzyloxy-4-octyloxybenzene (13.85 g, 44.33 mmol) was placed in a flask along with EtOH (95%, aqueous, 150 mL) and EtOAc (150 mL). With stirring, Pd/C

(0.95 g, 10 wt% wet, Degussa type) was added to the flask. The reaction mixture was then degassed by being placed under house vacuum for 30 minutes before being placed under an atmosphere of H2. The next day, the reaction had taken in approximately 1250 mL of H2 (55.8 mmol). The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The crude material was then recrystallized from petroleum ether before being dried in vacuo overnight (P2O5 and wax shavings) to yield 6.42 g (65%) of

1 white crystals. H NMR (400 MHz, CDCl3): δ 0.88 (t, 3H, J = 6.8 Hz), 1.22-1.39 (m,

8H), 1.44 (app quint, 2H, J = 7.3 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 3.89 (t, 2H, J = 6.6

67

Hz), 4.43 (s, 1H), 6.75 (d, 2H, J = 9.2 Hz), 6.79 (d, 2H, J = 9.6 Hz). mp = 58.9-60.8 °C

(lit.54 58.5-59.0 °C).

1-Benzyloxy-4-decyloxybenzene (62b)

4-Benzyloxyphenol (8.27 g, 41.3 mmol), 1-bromodecane (13.47 g, 60.90 mmol), and potassium carbonate (11.81 g, 85.45 mmol) were all placed in a 500 mL round- bottom flask along with 2-butanone (170 mL). The mixture was brought to reflux with stirring and allowed to reflux and stir overnight. The next day, the reaction mixture was allowed to cool to room temperature and was vacuum filtered. The filtered solid was then washed with 2-butanone (100 mL), and the filtrate was washed with aqueous NaOH

(1M, 3x100 mL), deionized water (2x100 mL), dried over MgSO4, and vacuum filtered.

The solvent was then removed in vacuo before the material was recrystallized from petroleum ether in two crops. The two crops were dried in vacuo overnight (P2O5) to give 8.19 g of white crystals. The material contained a significant portion of starting phenol by 1H NMR, so it was taken up in 2-butanone (100 mL) along with 1- bromodecane (4.04 g, 18.3 mmol) and potassium carbonate (5.65 g, 40.9 mmol). The mixture was brought to reflux and stirred for 48 hours before being allowed to cool to room temperature and vacuum filtered. The filtered solid was washed with 2-butanone

(100 mL), and solvent was removed in vacuo. The resulting white crystalline material showed no sign of starting phenol by 1H NMR, so the material was left to dry overnight

68

1 in vacuo (P2O5) to yield 6.36 g (45% yield) of white crystals. mp = 75.5-76.5 °C. H

NMR (400 MHz, CDCl3): δ 0.88 (t, 3H, J = 6.8 Hz), 1.22-1.38 (m, 12H), 1.44 (app quint,

2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 3.90 (t, 2H, J = 6.6 Hz), 5.01 (s, 1H), 6.82

(d, 2H, J = 9.2 Hz), 6.90 (d, 2H, J = 9.2 Hz), 7.28-7.45 (m, 5H). 13C NMR (100 MHz,

CDCl3): δ 153.54, 152.85, 137.36, 128.56, 127.88, 127.50, 115.81, 115.40, 70.71, 68.64,

31.93, 29.62, 29.59, 29.45, 29.41, 29.35, 26.09, 22.71, 14.15.

4-Decyloxyphenol (63b)

1-Benzyloxy-4-decyloxybenzene (6.25 g, 18.4 mmol) was placed in a flask along with EtOH (95%, aqueous, 75 mL) and EtOAc (75 mL). With stirring, Pd/C (0.48 g, 10 wt% wet Degussa type) was added to the mixture before being degassed by being placed under house vacuum for 30 minutes. The reaction mixture was placed under an atmosphere of H2 and stirred at ambient temperature for ~20 hours, at which point, the mixture had taken in approximately 600 mL of H2 gas (26.8 mmol). The mixture was then filtered through Celite and the filter was thoroughly washed with EtOAc (~100 mL).

The filtrate was then concentrated in vacuo. The crude material was recrystallized from petroleum ether (all crude material was taken up in solvent which had been warmed to

~60° C, the solution was then allowed to cool to room temperature before being cooled in the refrigerator). The filtered crystalline product was dried overnight in vacuo (P2O5) to

1 give 2.01 g (44% yield) of white crystals. H NMR (400 MHz, CDCl3): δ 0.88 (t, 3H, J =

69

6.8 Hz), 1.21-1.38 (m, 12H), 1.44 (app quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, J = 7.0

Hz), 3.89 (t, 2H, J = 6.6 Hz), 4.34 (br s, 1H), 6.74 (d, 2H, J = 9.2 Hz), 6.78 (d, 2H, J =

8.8 Hz). mp = 70.7-71.6 °C (lit.54 68.5-69.0 °C)

1-Benzyloxy-4-dodecyloxybenzene (62c)

4-Benzyloxyphenol (6.24 g, 31.2 mmol), 1-bromododecane (11.46 g, 45.98 mmol), and potassium carbonate (9.36 g, 67.7 mmol) were all placed into a 500 mL pear- shaped flask along with 2-butanone (150 mL). The mixture was brought to reflux and stirred overnight. The next day, the mixture was allowed to cool briefly before filtering off the potassium salts. The filtered solid was washed with 2-butanone (100 mL) and the solvent was removed in vacuo. The resulting crude material (17.15 g) was recrystallized from petroleum ether: (i) the material was taken up in a minimum amount of warm petroleum ether, and a few mL of additional petroleum ether was added, (ii) the resulting solution was cooled in an ice-water bath for ~30 minutes before collecting the crystallized material by vacuum filtration, and (iii) the filtered crystalline product was washed with room temperature petroleum ether and was then allowed to air dry on the filter for ~30 minutes. The resulting product was then dried overnight in vacuo (P2O5 and wax shavings) to give 10.26 g (89% yield) of white crystals. mp = 78.5-80.0 °C. 1H

NMR (400 MHz, CDCl3): δ 0.88 (t, 3H, J = 6.8 Hz), 1.19-1.38 (m, 16H), 1.44 (app quint,

2H, J = 7.1 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 3.89 (t, 2H, J = 6.6 Hz), 5.01 (s, 2H), 6.82

70

(d, 2H, J = 9.2 Hz), 6.89 (d, 2H, J = 9.2 Hz), 7.29-7.45 (m, 5H). 13C NMR (100 MHz,

CDCl3): δ 153.54, 152.85, 137.36, 128.56, 127.88, 127.50, 115.81, 115.40, 70.71, 68.64,

31.95, 29.69, 29.67, 29.63, 29.45, 29.41, 29.39, 26.09, 22.73, 14.16. [Note: One carbon signal is believed to be missing due to aliphatic overlap.].

4-Dodecyloxyphenol (63c)

1-Benzyloxy-4-dodecyloxybenzene (9.96 g, 27.0 mmol) was added to a 500 mL flask along with EtOAc (150 mL) and EtOH (95%, aqueous, 150 mL). Pd/C (0.78 g, 10 wt% wet Degussa type) was then added to the mixture in several small portions with stirring. The stirred mixture was then degassed by being placed under house vacuum for

90 minutes before being put under an atmosphere of H2. After 3 hours, the system had taken in ~350 mL of H2 (approximately 15.6 mmol). The mixture was then allowed to stir overnight. The next day, the system had taken in a total of ~750 mL H2

(approximately 33.5 mmol). The reaction mixture was then filtered through Celite and the filter was washed with EtOH (100 mL). The solvent was removed in vacuo, and the crude material was recrystallized from petroleum ether before being dried in vacuo

1 overnight (P2O5 and wax shavings) to give 6.58 g (87% yield) of white crystals. H NMR

(400 MHz, CDCl3): δ 0.88 (t, 3H, J = 6.8 Hz), 1.21-1.39 (m, 16H), 1.44 (app quint, 2H, J

= 7.6 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 3.89 (t, 2H, J = 6.6 Hz), 4.34 (s, 1H), 6.75 (d, 2H,

J = 9.2 Hz), 6.79 (d, 2H, J = 9.6 Hz). mp = 76.8-78.3 °C (lit.54 77.0-78.0 °C).

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Figure 3.2: Synthesis of sodium 1,3,4-thiadiazole-2-carboxylate salt

Methyl 4-octyloxybenzoate (41)

Methyl 4-hydroxybenzoate (29.92 g, 0.1966 mol), potassium carbonate (54.78 g,

0.3964 mol), and 1-bromooctane (38.33 g, 0.1985 mol) were all placed in a 1000 mL round-bottom flask along with 2-butanone (350 mL). The mixture was stirred and heated to reflux overnight. The next day, the mixture was allowed to cool to room temperature before the potassium salts were filtered off. The solvent was removed in vacuo and the crude product was recrystallized from petroleum ether. Due to the low melting point of the target material, the following procedure for recrystallization was used: (i) a small amount of petroleum ether, a stir bar, and a thermometer were all placed in the flask

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containing the material, (ii) the mixture was carefully warmed to ~30 °C with a heat gun,

(iii) small portions of petroleum ether were added while maintaining a temperature of ~

30 °C until all solids had been dissolved, and (iv) the stir bar and thermometer were removed before placing the flask in an ice-water bath for ~15 minutes to induce crystallization. The crystals were then collected via vacuum filtration and washed with cold petroleum ether. Over two crops, 36.21 g (69% yield) of a white, waxy solid was

1 collected. H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 7.0 Hz), 1.23-1.40 (m, 8H),

1.46 (app quint, 2H, J = 7.3 Hz), 1.80 (quint, 2H, J = 7.1 Hz), 3.88 (s, 3H), 4.00 (t, 2H, J

= 6.6 Hz), 6.90 (d, 2H, J = 8.8 Hz), 7.98 (d, 2H, J = 9.2 Hz). mp = 31.5-34.0 °C

4-Octyloxybenzohydrazide (42)

Methyl 4-octyloxybenzoate (43.54 g, 0.1647 mol), hydrazine monohydrate (165 mL, d = 1.032 g/mL at 25 °C, 3.40 mol), and EtOH (150 mL) were all placed in a 1000 mL round-bottom flask. The mixture was stirred and heated at reflux overnight. The next day, the mixture was allowed to cool to room temperature. The resulting solid was collected via vacuum filtration and was thoroughly washed with deionized water. The material was then dried overnight in vacuo (P2O5) to yield 42.23 g (97% yield) of a white

1 crystalline solid. H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 7.0 Hz), 1.23-1.40 (m,

8H), 1.46 (app quint, 2H, J = 7.2 Hz), 1.79 (quint, 2H, J = 7.1 Hz), 3.99 (t, 2H, J = 6.6

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Hz), 4.08 (br s, 2H), 6.92 (d, 2H, J = 8.8 Hz), 7.38 (br s, 1H), 7.70 (d, 2H, J = 8.8 Hz). mp = 88.5-90.0 °C (lit.33 90-91 °C).

1-(Ethyl oxalyl)-2-(4-octyloxybenzoyl)diazane (43)

A 100-mL pear-shaped flask was oven-dried for several hours and cooled under argon. 4-Octyloxybenzohydrazide (1.01 g, 3.82 mmol) was added to the flask and dissolved in anhydrous THF (20 mL). The solution was allowed to stir under argon for several minutes before adding anhydrous Et3N (0.80 mL, d = 0.726 g/mL at 25 °C, 5.7 mmol) in a single portion. The solution was then stirred for about 10 minutes before ethyl oxalyl chloride (0.51 mL, d = 1.222 g/mL at 25 °C, 4.5 mmol) was added in a dropwise fashion over a course of 10 minutes (each addition caused the evolution of a thick white gas and formation of a white precipitate). The mixture was stirred under argon at room temperature for 48 hours before a small portion was removed for NMR analysis, revealing that most of the material formed was product. The amine salt was vacuum filtered off and the filtered solid was washed with THF (50 mL). To the filtrate was added EtOH (50 mL), and after stirring for 10 minutes, the solvent was removed in vacuo to give an off-white crystalline solid. The material was dried overnight in vacuo

(P2O5) to give 1.31 g (94%) of product as an off-white waxy solid showing only trace

1 1 impurities by H NMR. H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 7.0 Hz), 1.25-

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1.50 (m, 12H), 1.41 (t, 3H, J = 7.0 Hz), 1.80 (quint, 2H, J = 7.0 Hz), 4.00 (t, 2H, J = 6.6

Hz), 4.40 (q, 2H, J = 7.2 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.80 (d, 2H, J = 8.8 Hz). [Notes:

The NH resonances for this compound were not apparent. The 1H NMR spectrum showed the presence of some trace impurities, but it was used as is through the next step.]

Ethyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (44)

Nearly pure 1-(ethyl oxalyl)-2-(4-octyloxybenzoyl)diazane

(7.54 g, 20.7 mmol), which had been ground in a mortar and pestle and dried in vacuo overnight (P2O5 and wax shavings), was removed from a vacuum desiccator and immediately weighed out and placed in an oven-dried-argon-cooled 500 mL pear-shaped flask. After flushing the flask with argon for several minutes, the material was dissolved in anhydrous THF (150 mL) and stirred for several minutes at room temperature.

Lawesson’s reagent (5.36 g, 13.3 mmol) was then added to the solution in one portion.

The yellow solution was stirred under argon at room temperature for approximately 24 hours. TLC analysis showed complete consumption of the starting material. The solvent was removed in vacuo and the material sat overnight, the flask covered with a Kimwipe to prevent contamination. The material was taken up into THF (~80 mL) and the solution was divided in half. Each half was chromatographed separately. TLC analysis showed

10% EtOAc in petroleum ether to be a suitable solvent system for the separation of the product. (Rf of ~0.25).

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Column #1:

Half of the above product solution was deposited onto silica gel to give 13.59 g of a free flowing off-white powder (corresponding to 5.59 g of actual crude product). This material was purified by column chromatography (300 g silica gel, 10% EtOAc in petroleum ether). The following TLC graphic adequately summarizes the results:

Fractions B gave the most pure and most abundant amount of product (~2.7 g, as opposed to ~0.5 g from fractions C and D combined). Fractions B were combined, and the solvent was removed in vacuo, and the material was dried overnight in vacuo (P2O5) to give 2.48 g of off-white crystalline material.

Column #2:

Column #2 was run as described for column #1 to give similar results. Fractions

B were combined, the solvent was removed in vacuo, and the material was dried overnight in vacuo (P2O5) to give 2.38 g of off-white crystalline material.

Together, both columns gave a total of 4.86 g (65% yield) of off-white crystalline

1 material. H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 6.8 Hz), 1.23-1.41 (m, 8H), 1.47

(t, 3H, J = 7.0 Hz), 1.41-1.52 (quint [obscured by t at 1.47], 2H), 1.82 (quint, 2H, J = 7.1

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Hz), 4.03 (t, 2H, J = 6.6 Hz), 4.53 (q, 2H, J = 7.2 Hz), 6.99 (d, 2H, J = 8.8 Hz), 7.96 (d,

2H, J = 8.8 Hz). mp = 102.5-104.5 °C (lit.33 105.3 °C).

Sodium 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (45)

A solution of EtOH (100 mL, 95% aqueous) and deionized water (35 mL) was adjusted to pH = 14 (as per pH paper test) with solid NaOH. This solution was then poured into a 250 mL round-bottom flask containing ethyl 5-(4-octyloxyphenyl)-1,3,4- thiadiazole-2-carboxylate (4.8247 g, 13.310 mmol) with stirring. The mixture was allowed to stir at room temperature for 48 hours, when TLC analysis revealed that no starting material remained (single spot sitting at the baseline). The crude product was collected by vacuum filtration, washed with Et2O (200 mL), and dried in vacuo overnight

(P2O5). During the process of opening the desiccator, a small amount of another material

(4-octyloxyphenol) contaminated the product. The product was then washed thoroughly with cold Et2O (~100 mL) and dried in vacuo overnight (P2O5) to give 4.33 g (91% yield) of a white powder. It was noted that after sitting in an amber bottle for approximately 48 hours, the material had taken on a faint pink color. 1H NMR analysis of the newly pink material was found to be identical to the white material, and this phenomenon was noted

1 in two separate preparations of the material. H NMR (400 MHz, DMSO-d6): δ 0.87 (t,

3H, J = 6.8 Hz), 1.20-1.37 (m, 8H), 1.42 (app quint, 2H, J = 7.3 Hz), 1.73 (quint, 2H, J =

6.9 Hz), 4.04 (t, 2H, J = 6.6 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7.86 (d, 2H, J = 8.8 Hz).

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4-Octyloxyphenyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (48a)

Unless otherwise noted, once the three-neck flask was cooled to -8 °C, a temperature between -6 and -8 °C was maintained throughout the course of the reaction, including during the addition of any reagents.

An oven-dried 50 mL round-bottom flask was cooled under argon. 4-

Octyloxyphenol (0.279 g, 1.25 mmol) was placed in the flask and dissolved in anhydrous toluene (5.0 mL) and allowed to stir under argon at room temperature (solution A).

Separately, a second oven-dried 50 mL three-neck round-bottom flask was cooled under argon. Sodium 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (0.5036 g, 1.413 mmol) was placed in the flask, along with anhydrous toluene (5.0 mL). The mixture was sonicated while under argon for approximately 30 minutes before being cooled to -8 °C.

Thionyl chloride (0.18 mL, d = 1.631 g/mL at 25 °C, 2.5 mmol, used as received) was then added dropwise over the course of about 2 minutes. The mixture was then allowed to stir for 90 minutes before the reaction mixture was diluted dropwise with anhydrous toluene (8 mL, pre-chilled in freezer). The reaction was allowed to stir for another 60 minutes before anhydrous pyridine (0.24 mL, d = 0.978 g/mL, 3.0 mmol) was added in two small portions. Next, the solution of 4-octyloxyphenol in toluene (solution A above) was added to the reaction mixture dropwise. The reaction was then allowed to stir for 20 hours before being exposed to the ambient atmosphere and allowed to slowly warm to

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room temperature. The mixture was then filtered through Celite, which was thoroughly washed with toluene (100 mL). The filtrate was then washed with saturated aqueous

NaHCO3 (100 mL), causing a solid to form, which subsequently caused a persistent emulsion. Therefore, to remove the emulsion, the whole mixture was passed through the same Celite plug as before, which was again washed thoroughly with toluene (100 mL).

The filtered mixture was then washed again with saturated aqueous NaHCO3 (100 mL) and deionized water (2x100 mL). The combined aqueous washings were then extracted with CH2Cl2 (2x100 mL), and the combined organic washings were dried over MgSO4, and filtered in vacuo. The solvent was removed in vacuo to give a highlighter-yellow solid. Crude 1H NMR analysis revealed a mixture containing both the desired product and protodecarboxylated byproduct in a 1:1.6 ratio.

An attempt was made to purify the material by column chromatography (50 g silica gel, 15% EtOAc in petroleum ether, the silica gel was stirred in a solution of 10% triethylamine in petroleum ether before packing, and the column was washed with one column volume worth of eluent before loading the product), but there was very poor separation. Fractions containing all of the resulting spots were combined and an attempt was made to isolate each spot via preparative TLC. The plates were pre-treated with a

10% solution of triethylamine in petroleum ether before being eluted with 10% EtOAc in petroleum ether. Two runs of approximately 15 mg each were performed, and each gave four separate bands (A through D, more polar to less polar). Only the most polar band,

A, gave evidence of product by 1H NMR, but the purity of the band was poor (1:0.87

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product:phenol byproduct). The other bands gave varying combinations of starting phenol and decarboxylated material.

Figure 3.3: Synthesis of final liquid crystal targets

4-Octyloxyphenyl (N’-(4-octyloxyphenylcarbonyl)hydrazinecarbonyl)formate (68a)

Under argon, oxalyl chloride (10.0 mL, d = 1.5 g/mL at 20 °C, 118 mmol) was placed into an oven-dried argon-cooled round-bottom flask. 4-Octyloxyphenol (0.5036 g, 2.265 mmol) was then added to the flask with stirring in a single portion, forming a deep orange-red solution. The solution was heated under reflux; however, it was noted that the solution had taken on a pale yellow color after 90 minutes of reflux.

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The next day, the flask was cooled and flushed with argon for approximately 10 minutes before removing excess oxalyl chloride in vacuo (rotary evaporator). This step was done as quickly as (safely) possible. Immediately after removing the flask from the rotary evaporator, the flask was stoppered and purged with argon for a further 30 minutes

(amount of time was for convenience). The crude acyl chloride was diluted with anhydrous toluene (10 mL), which was also removed in vacuo (to ensure complete removal of oxalyl chloride) to give a deep yellow oil. The flask containing the oil (which solidified upon standing) was stoppered and purged with argon until further use (flask A).

4-Octyloxybenzohydrazide (0.6020 g, 2.277 mmol) was added to an oven-dried argon-cooled flask. Under argon, the material was taken up in anhydrous THF (40 mL).

Anhydrous Et3N (0.48 mL, d = 0.726 g/mL at 25 °C, 3.4 mmol) was then added to the flask in a single portion and the solution was allowed to stir briefly before the next addition. A solution of the crude acyl chloride (flask A) was prepared by adding anhydrous THF (20 mL) to the flask under argon, and this solution was added to the benzohydrazide solution in a dropwise manner (room temperature, over approximately 20 minutes). The addition caused a white precipitate to form. The mixture was stirred under argon for 45 minutes and was then vacuum filtered (the flask and filter were rinsed with an additional 20 mL of THF). The filtrate was concentrated in vacuo (rotary evaporator).

The residual material was dried in a vacuum desiccator overnight (P2O5 and wax shavings) to give 1.1318 g of a waxy yellow solid. 1H NMR revealed a mixture that was a mixture of product to starting phenol in a 1.8:1 ratio. Despite this, the material was used crudely through the next step due to difficulty in further purification. 1H NMR (400

81

MHz, CDCl3): δ 0.85-0.93 (t x 2 [overlapping], 6H), 1.22-1.40 (m, 16H), 1.40-1.51 (quint x 2 [overlapping], 4H), 1.70-1.86 (quint x 2 [overlapping], 4H), 3.95 (t, 2H, J = 6.6 Hz),

4.02 (t, 2H, J = 6.6 Hz), 6.92 (d, 2H, J = 9.2 Hz), 6.96 (d, 2H, J = 8.8 Hz), 7.11 (d, 2H, J

= 9.2 Hz), 7.83 (d, 2H, J = 8.8 Hz), 8.84 (br s, 1H), 9.95 (br s, 1H). [Note: Peaks from impurities were excluded.]

4-Octyloxyphenyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (48a)

Under argon, crude 4-octyloxyphenyl (N’-(4- octyloxyphenylcarbonyl)hydrazinecarbonyl)formate (0.2560 g) was placed into an oven- dried argon-cooled flask. Anhydrous toluene (30 mL) was added with stirring.

Lawesson’s reagent (0.1192 g, 0.2947 mmol) was then added to the mixture in a single portion before it was brought to reflux in an oil bath. Once at reflux, all solids in the flask had been dissolved (orange/yellow solution). After refluxing for 4 hours, a sample was removed and 1H NMR analysis revealed that no starting material remained. Heating was then discontinued. Solvent was removed in vacuo (rotary evaporator), and the crude mixture was dried overnight (vacuum desiccator, P2O5 and wax shavings) to give 0.3706 g of a yellow solid. 1H NMR analysis revealed the intended product to be the major component, but the material needed further purification. The material was purified by column chromatography (10% EtOAc in petroleum ether, wet loaded in CH2Cl2) to give two fractions of similar purity (each had trace amounts of starting phenol present by 1H

82

NMR). The first fraction (A, 0.1038 g) had only one spot by TLC, but the second fraction (B, 0.0768 g) had an extra spot.

The total mass of synthetically pure material obtained from the column was 0.1806 g

(65% yield for three steps from 4-octyloxyphenol). An analytically pure sample was required for mesogenic studies. Recrystallization from DME followed by hot filtration gave 0.0687 g (25% yield for three steps from 4-octyloxyphenol) of off-white needles.

Transitions (°C) Cryst I 100.7 Cryst II 105.1 SmC 175.4 N 187.8 Iso Liq (rec. 85.2). 1H

NMR (400 MHz, CDCl3): δ 0.89 (t, 6H, J = 6.8 Hz), 1.24-1.41 (m, 16H), 1.41-1.52 (m,

4H), 1.79 (quint, 2H, J = 6.6 Hz), 1.83 (quint, 2H, J = 6.9 Hz), 3.96 (t, 2H, J = 6.6 Hz),

4.04 (t, 2H, J = 6.6 Hz), 6.94 (d, 2H, J = 9.2 Hz), 7.01 (d, 2H, J = 9.2 Hz), 7.20 (d, 2H, J

13 = 9.2 Hz), 8.00 (d, 2H, J = 8.8 Hz). C NMR (100 MHz, CDCl3): δ 173.06, 162.53,

158.00, 157.80, 157.45, 143.50, 130.14, 122.02, 121.63, 115.28, 115.17, 68.45, 68.41,

31.80, 29.34, 29.31, 29.23, 29.08, 26.03, 25.97, 22.65, 14.10. [Note: Five carbon signals are believed to be absent due to accidental overlap in the aliphatic region.]

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4-Decyloxyphenyl (N’-(4-octyloxyphenylcarbonyl)hydrazinecarbonyl)formate

(68b)

Under argon, an oven-dried argon-cooled flask was charged with oxalyl chloride

(10.2 mL, d = 1.5 g/mL at 20 °C, 121 mmol). 4-Decyloxyphenol (0.5021 g, 2.005 mmol) was added to the flask with stirring in a single portion. The resulting deep orange-red solution was then warmed to reflux in an oil bath overnight while under argon. The next day, heating was discontinued and the flask was allowed to cool to room temperature before excess oxalyl chloride was removed in vacuo (rotary evaporator). The flask was then immediately purged with argon and was diluted with anhydrous toluene (10 mL).

The toluene was then removed in vacuo (rotary evaporator, to ensure complete removal of oxalyl chloride) to give a deep yellow oil which solidified upon purging with argon.

The flask containing the crude acyl chloride was allowed to sit under argon until further use (approximately 3 hours, for convenience, flask A).

Under argon, 4-octyloxybenzohydrazide (0.5344 g, 2.021 mmol) was placed into an oven-dried argon-cooled round-bottom flask and taken up in anhydrous THF (40 mL).

Anhydrous Et3N (0.41 mL, d = 0.726 g/mL at 25 °C, 2.9 mmol) was added to the flask in a single portion and the solution was allowed to stir briefly. A solution of the crude acyl chloride (flask A) was prepared by taking the material up in anhydrous THF (20 mL), and

84

this solution was added to the benzohydrazide solution dropwise via syringe pump at room temperature (approximately 25 minutes). After the addition (which caused the formation of a precipitate), the mixture was allowed to stir for 60 minutes at room temperature before the mixture was vacuum filtered. The solvent was removed in vacuo

(rotary evaporator) to give 1.17 g of a waxy yellow solid. 1H NMR analysis revealed a mixture composed of product and starting phenol in a 1.4:1 ratio. The material was used crudely through the next step due to difficulty in purification. 1H NMR (400 MHz,

CDCl3): δ 0.84-0.93 (t x 2 [overlapping], 6H), 1.22-1.41 (m, 20H), 1.41-1.51 (quint x 2

[overlapping], 4H), 1.70-1.87 (quint x 2 [overlapping], 4H), 3.95 (t, 2H, J = 6.6 Hz), 4.01

(t, 2H, J = 6.6 Hz), 6.92 (d, 2H, J = 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 7.11 (d, 2H, J = 9.2

Hz), 7.83 (d, 2H, J = 8.8 Hz), 8.92 (br s, 1H), 9.93 (br s, 1H). [Note: Peaks from impurities were excluded.]

4-Decyloxyphenyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (48b)

A flask containing crude 4-decyloxyphenyl (N’-(4- octyloxyphenylcarbonyl)hydrazinecarbonyl)formate (1.17 g) was dried under high vacuum (P2O5 and wax shavings) for ~10 hours prior to the reaction being set up. The flask was purged with argon briefly before adding anhydrous toluene (90 mL).

Lawesson’s reagent (0.4986 g, 1.233 mmol) was then added to the flask in one portion.

The mixture (cloudy/yellow) was warmed to reflux in an oil bath with stirring while

85

under argon. After heating under reflux for 2 hours (some solid materials were still not fully dissolved and the reaction mixture had a slightly cloudy appearance), a sample was removed for analysis by 1H NMR, which revealed that no starting material remained. At a total reaction time of 2.75 hours, heating was discontinued and the flask was allowed to cool to room temperature before removing the solvent in vacuo (rotary evaporator, followed by house vacuum for ~2 hours) to give 1.59 g of a waxy yellow solid which was stored under argon until purification.

The crude mixture was purified by column chromatography (10% EtOAc in petroleum ether, wet loaded in CH2Cl2 due to sparing solubility in eluent) to give two fractions. Fraction A (0.3102 g) contained primarily the expected product, but also contained a significant amount of 4-decyloxyphenol. Fraction B (0.1179) was synthetically pure, although trace impurities were observed by 1H NMR analysis which contradicts what was expected due to the results of the TLC plate shown below:

The fractions were recrystallized (separately) from DME to give 0.1787 g and

0.0637 g, respectively, of pure material. (0.2424 g, 21% yield for three steps from 4- decyloxyphenol). Transitions (°C) Cryst I 100.1 SmC 175.3 N 183.5 Iso Liq (rec. 84.9).

1 H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 6.6 Hz), 0.90 (t, 3H, J = 6.6 Hz), 1.22-

1.42 (m, 20H), 1.42-1.52 (m, 4H), 1.79 (quint, 2H, J = 6.8 Hz), 1.83 (quint, 2H, J = 6.7

86

Hz), 3.97 (t, 2H, J = 6.6 Hz), 4.04 (t, 2H, J = 6.6 Hz), 6.94 (d, 2H, J = 9.2 Hz), 7.01 (d,

2H, J = 8.8 Hz), 7.20 (d, 2H, J = 9.2 Hz), 8.00 (d, 2H, J = 9.2 Hz). 13C NMR (100 MHz,

CDCl3): δ 173.07, 162.55, 158.02, 157.81, 157.47, 143.51, 130.15, 122.04, 121.65,

115.30, 115.19, 68.47, 68.43, 31.91, 31.81, 29.59, 29.40, 29.33, 29.23, 29.10, 26.04,

25.99, 22.69, 22.67, 14.11. [Note: Four carbon signals are believed to be absent due to accidental overlap in the aliphatic region.]

4-Dodecyloxyphenyl (N’-(4-octyloxyphenylcarbonyl)hydrazinecarbonyl)formate

(68c)

Under argon, an oven-dried argon-cooled round-bottom flask was charged with oxalyl chloride (10.0 mL, d = 1.5 g/mL at 25 °C, 118 mmol). 4-Dodecyloxyphenol

(0.5111 g, 1.836 mmol) was added with stirring in a single portion to give a deep orange- red mixture. Upon warming to reflux, all of the solids dissolved, and the solution was refluxed overnight.

The next day, heating was discontinued and the flask was cooled to room temperature before removing excess oxalyl chloride in vacuo (rotary evaporator), and the crude acyl chloride was purged with argon and then stored under argon for ~2 hours (for convenience) before being diluted with anhydrous toluene (10 mL). The toluene was

87

then removed in vacuo (rotary evaporator, to ensure complete removal of oxalyl chloride) and the flask was then purged with argon until further use (flask A).

Under argon, 4-octyloxybenzohydrazide (0.4915 g, 1.859 mmol) was added to an oven-dried argon-cooled round-bottom flask and taken up in anhydrous THF (40 mL).

Anhydrous Et3N (0.40 mL, d = 0.726 g/mL 25 °C, 2.9 mmol) was then added to the flask in a single portion. A solution of the crude acyl chloride was prepared by taking up the material (flask A) in anhydrous THF (20 mL), and this solution was added to the benzohydrazide solution dropwise via syringe pump at room temperature (over 20 minutes, this addition caused formation of a white precipitate). After being allowed to stir for 60 minutes, the mixture was vacuum filtered and the solvent was removed in vacuo (rotary evaporator). The product was then dried overnight in a high vacuum

1 desiccator (w/ P2O5) to give 1.21 g of a waxy yellow solid. H NMR analysis revealed a mixture of product and starting phenol in a 4.4:1 ratio. The material was stored under

1 argon until further use. H NMR (400 MHz, CDCl3): δ 0.85-0.93 (t x 2 [overlapping],

6H), 1.20-1.40 (m, 24H), 1.40-1.51 (quint x 2 [overlapping], 4H), 1.71-1.85 (quint x 2

[overlapping], 4H), 3.94 (t, 2H, J = 6.6 Hz), 4.00 (t, 2H, J = 6.4 Hz), 6.90 (d, 2H, J = 9.2

Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.09 (d, 2H, J = 8.8 Hz), 7.84 (d, 2H, J = 8.4 Hz), 9.15 (br s, 1H), 9.88 (br s, 1H). [Note: Peaks from impurities were excluded.]

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4-Dodecyloxyphenyl 5-(4-octyloxyphenyl)-1,3,4-thiadiazole-2-carboxylate (48c)

A flask containing crude 4-dodecyloxyphenyl (N’-(4- octyloxyphenylcarbonyl)hydrazinecarbonyl)formate (1.21 g) was purged with argon briefly before being charged with anhydrous toluene (100 mL). The mixture was stirred briefly under argon before adding Lawesson’s reagent (0.5065 g, 1.252 mmol) in a single portion. The mixture was warmed to reflux in an oil bath, slowly dissolving all the solids present. The mixture was heated under reflux for approximately 2 hours before removing a sample for 1H NMR analysis, which revealed no remaining starting material. Heating was discontinued and the flask was allowed to cool to room temperature before removing the solvent in vacuo (rotary evaporator) to give 1.70 g of crude product. The crude product was purified by column chromatography (10% EtOAc in petroleum ether, wet loaded in CH2Cl2) to give two fractions (A, 0.370 g and B, 0.270 g) of nearly identical purity by 1H NMR (59% yield for three steps from 4-dodecyloxyphenol), although they differed in their TLC profiles, as shown below:

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To obtain analytically pure materials for mesogenic studies, the two fractions were combined, recrystallized from DME, and hot filtered to give 0.387 g (35% for three steps from 4-dodecyloxyphenol) of a white powder. Transitions (°C) Cryst 98.9 SmC

1 174.3 N 180.1 Iso Liq (rec. 84.4). H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 6.8

Hz), 0.90 (t, 3H, J = 6.6 Hz), 1.20-1.42 (m, 24H), 1.42-1.52 (m, 4H), 1.79 (quint, 2H, J =

6.9 Hz), 1.83 (quint, 2H, J = 6.7 Hz), 3.97 (t, 2H, J = 6.6 Hz), 4.04 (t, 2H, J = 6.6 Hz),

6.94 (d, 2H, J = 8.8 Hz), 7.01 (d, 2H, J = 8.8 Hz), 7.20 (d, 2H, J = 9.2 Hz), 8.00 (d, 2H, J

13 = 8.8 Hz). C NMR (100 MHz, CDCl3): δ 173.07, 162.55, 158.02, 157.81, 157.47,

143.52, 130.15, 122.04, 121.65, 115.30, 115.19, 68.48, 68.43, 31.93, 31.81, 29.67, 29.65,

29.61, 29.59, 29.40, 29.36, 29.33, 29.23, 29.10, 26.04, 25.99, 22.70, 22.67, 14.11. [Note:

Two carbon signals are believed to be absent due to accidental overlap in the aliphatic region.]

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