DESIGN AND SYNTHESIS STRATEGIES FOR SMALL MOLECULE …

The Pennsylvania State University

The Graduate School

Eberly College of Science

DESIGN AND SYNTHESIS STRATEGIES FOR SMALL MOLECULE

AND POLYMER AMPLIFICATION REAGENTS

A Dissertation in

Chemistry

by

Travis J. Cordes

2016 Travis J. Cordes

Submitted in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy

December 2016

The dissertation of Travis J. Cordes was reviewed and approved* by the following:

Scott T. Phillips

Associate Professor of Chemistry

Dissertation Advisor

Chair of Committee

Przemyslaw Maslak

Associate Professor of Chemistry

Robert Rioux

Associate Professor of Chemical Engineering

Kenneth S. Feldman

Professor of Chemistry

Chair of the Graduate Program of the Department of Chemistry

*Signatures are on file in the Graduate School

iii

ABSTRACT

Self-replicating and self-amplifying systems provide the foundation for the

evolution of life and are an inherent component of many biological processes. For over a

century, scientists have studied these reactions in an attempt to elucidate the mechanisms

responsible for the origin of life, as well as to create chemical reaction systems that

mimic these biological phenomena. However, relatively few synthetic amplification

reactions are used in commercial applications due to their complexity, or because of

limitations such as slow rates of reaction and thermal instability.

Amplification reactions are currently sought after in the context of creating

reagents for point-of-need assays and stimuli-responsive materials. Reactions that

amplify the presence of a molecular signal are particularly attractive due to their ability to

produce a large readout signal in response to trace quantities of an analyte. In particular,

this dissertation will focus on the development of two approaches to signal amplification:

i) autocatalytic reagents and ii) depolymerizable polymers.

More specifically, this dissertation will address methods for accelerating the rate

of various signal amplification reactions. This includes i) studying the effects of

proximity and effective concentration on a base-mediated autocatalytic reaction; ii)

designing novel polymer backbones for rapid depolymerization; iii), increasing the rate of

solid-state depolymerization in aqueous environments; and iv) mechanoresponsive

properties of depolymerizable polymers.

iv

TABLE OF CONTENTS

List of Figures .......................................................................................................................... vii

Acknowledgements .................................................................................................................. xvi

Chapter 1: Base-Mediated Autocatalytic Signal Amplification......................................... 1

1.1 Introduction ................................................................................................................ 1

1.2 Catalytic Amplification Systems................................................................................ 2

1.2.1 Transition Metal Catalytic Amplification ....................................................... 2

1.2.2 Enzyme-Based Amplification ......................................................................... 5

1.2.3 Summary of Catalytic Amplification .............................................................. 6

1.3 Autocatalytic Amplification ....................................................................................... 6

1.3.1 Introduction to Autocatalysis .......................................................................... 6

1.3.2 Examples of Autocatalysis .............................................................................. 8

1.3.3 Limitations of Amplification Reagent 1-13 .................................................... 12

1.4 Experimental Design .................................................................................................. 12

1.5 Results and Discussion ............................................................................................... 15

1.5.1 Synthesis of the Reagents ................................................................................ 15

1.5.2 LCMS Mechanistic Studies ............................................................................. 16

1.5.3 UV/Vis Kinetic Studies ................................................................................... 18

1.6 Conclusion ................................................................................................................. 23

1.7 References .................................................................................................................. 24

Chapter 2: Head-to-Tail Depolymerizable Polymers ........................................................ 27

2.1 Introduction to Depolymerizable Polymers ............................................................... 27

2.1.1 Classification of Depolymerization Mechanisms ............................................ 28

2.1.2 Continuous, Reaction-Based Depolymerization ............................................. 30

2.1.2.1 CDr Poly(carbamates) .......................................................................... 31

2.1.2.2 CDr Poly(benzyl ethers) ...................................................................... 34

2.1.2.3 Intramolecular Cyclizing CDr Polymers ............................................. 36

2.1.2.4 CDr Poly(phthalaldehyde) ................................................................... 38

2.1.2.5 CDr Poly(glyoxalates) ........................................................................ 39

v

2.1.3 Summary of CDr Polymers ............................................................................. 41

2.2 Efforts to Improve the Rate of Quinone Methide Elimination ................................... 41



2.4.1 Synthesis and Testing of a Model Furan Repeating Unit ................................ 45

2.4.2 Synthesis of Furan-based Poly(carbamates) .................................................... 50

2.4.3 Summary of 2-furylcarbamates ....................................................................... 50

2.4.4 Synthesis and Testing of a Model Thiophene Repeating Unit ........................ 52

2.4.5 Synthesis of Thiophene-based Poly(carbamates) ............................................ 54

2.5 Conclusion and Future Directions ............................................................................. 55

2.6 References.................................................................................................................. 56

Chapter 3: Solid-State Depolymerization of Poly(benzyl ethers) ...................................... 63

3.1 Introduction ................................................................................................................ 63



3.3.1 Synthesis of the Monomers ............................................................................. 70

3.3.2 Synthesis of Poly(benzyl ethers) ..................................................................... 71

3.3.3 Solution Phase Studies for Selective Depolymerization of Poly(benzyl

ethers) ............................................................................................................... 72

3.3.4 Solid-State Depolymerization of Poly(benzyl ethers) ..................................... 74

3.3.5 Verification of the Head-to-Tail Depolymerization Mechanism .................... 77

3.3.6 Characterization of Material Properties .......................................................... 76

3.4 Conclusions................................................................................................................ 82

3.5 References.................................................................................................................. 83

Chapter 4: Mechanically-Induced Responses of CDr Polymers ........................................ 84

4.1 Introduction of Mechanoresponsive Materials ........................................................... 84

4.2 Mechanochemical Responses of CDr Polymers ......................................................... 90



4.4.1 Responses of Multiple Polymer Backbones .................................................... 93

vi

4.4.2 Mechanistic Studies and Trapping Experiments ............................................. 96

4.4.3 Effect of Degree of Polymerization on Rate of Cleavage ............................... 100

4.4.4 Cyclization Hypothesis ................................................................................... 102

4.5 Conclusion and Future Directions .............................................................................. 104

4.6 References.................................................................................................................. 105

Chapter 5: Materials, Methods, Experimental Procedures, and Characterization ......... 109

5.1 Materials..................................................................................................................... 109

5.2 Methods ...................................................................................................................... 110

5.3 Chapter 1: Experimental Procedures and Characterization ........................................ 112

5.4 Chapter 2: Experimental Procedures and Characterization ....................................... 123



5.7 References ................................................................................................................. 154

Appendix A: NMR Spectra .................................................................................................. 155

Chapter 1 NMR Spectra ................................................................................................... 155



Appendix B: Data Tables for Kinetics Experiments .......................................................... 216

Data for Chapter 1 ............................................................................................................ 216

Data for Chapter 2 ............................................................................................................ 220

Data for Chapter 3 ............................................................................................................ 225

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LIST OF FIGURES

Chapter 1

Figure 1-1. Schematic depiction of catalytic signal amplification .......................................... 2

Figure 1-2. Catalytic signal amplification by Anslyn ............................................................. 3

Figure 1-3. Allosterically-regulated catalytic amplification by Mirkin .................................. 4

Figure 1-4. Enzymatic signal amplification by Rotello. ......................................................... 5

Figure 1-5. Schematic illustration of autocatalytic signal amplification ................................ 7

Figure 1-6. Allosterically-regulated autocatalysis by Mirkin. ................................................ 8

Figure 1-7. Autocatalytic fragmentation of reagent 1-9 by Ichimura ..................................... 9

Figure 1-8. Base-mediated autocatalysis for photo-induced cross-linking by Ichimura ......... 9

Figure 1-9. Base-mediated autocatalytic amplification reaction by Mohapatra ..................... 10

Figure 1-10. Tandem autocatalytic reaction for the detection of Pd(0) by Mohapatra ........... 11

Figure 1-11. Schematic depiction of the functional group proximity hypothesis ................... 13

Figure 1-12. Structures of three model autocatalytic reagents. ............................................... 14

Figure 1-13. Revised reaction mechanism for base-mediated autocatalytic amplification ..... 14

Figure 1-14. Synthetic scheme for reagent 1-25 ..................................................................... 15

Figure 1-15. Synthetic schemes for reagents 1-15, 1-16, and 1-17 ......................................... 16

Figure 1-16. Products of the autocatalytic reaction of 1-17 with piperidine ........................... 17

Figure 1-17. LCMS traces of the autocatalytic reaction of 1-17 with piperidine ................... 17

viii

Figure 1-18. Product concentration and composition data for the autocatalytic reaction of

1-17 with piperidine via LCMS .......................................................................... 18

Figure 1-19. Time lapsed UV/Vis data of the reaction of 1-15 with piperidine ..................... 19

Figure 1-20. Comparison of kinetics of autocatalytic reagents 1-15, 1-16, and 1-17 ............. 19

Figure 1-21. Graphs depicting relative reaction rates of reagents 1-15, 1-16, and 1-17 ......... 20

Figure 1-22. Structures of autocatalytic reagents and intermediates....................................... 21

Figure 1-23. Comparison of kinetics profiles of reagents and intermediates .......................... 22

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Chapter 2

Figure 2-1. Classification of four types of depolymerizable polymers ................................... 28

Figure 2-2. Schematic depiction of CDr poly(carbamate) depolymerization .......................... 31

Figure 2-3. A novel carbamate spacer for controlled release by Katzenellenbogen ............... 31

Figure 2-4. Dendritic amplification reagent 2-2 by Shabat ..................................................... 32

Figure 2-5. Synthesis of linear poly(carbamate) 2-4 by Shabat .............................................. 31

Figure 2-6. Schematic depitction of CDr poly(benzyl ether) depolymerization ..................... 34

Figure 2-7. Selective disassembly of benzyl ether oligomer 2-5 by McGrath ........................ 34

Figure 2-8. Synthesis and depolymerization of poly(benzyl ether) 2-7 by Olah .................... 35

Figure 2-9. Schematic depiction of intramolecular cyclizing CDr polymers .......................... 36

Figure 2-10. Schematic depiction of CDr poly(phthalaldehyde) depolymerization ................ 38

Figure 2-11. Illustration of the selective depolymerization of patterned plastics ................... 39

Figure 2-12. Schematic depiction of CDr poly(ethyl glyoxalate) depolymerization .............. 39

Figure 2-13. Depolymerization of NVOC end-capped 2-13 ................................................... 40

Figure 2-14. Depolymerization mechanism of benzene-based CDr poly(carbamates) ........... 42

Figure 2-15. Release rates for carbamate spacers of varying aromaticity............................... 43

Figure 2-16. Proposed release mechanism of heterocyclic poly(carbamates) ........................ 44

Figure 2-17. Comparison of resonance energies in benzene, thiophene, and furan ................ 44

Figure 2-18. Synthetic scheme for model furan reagent 2-23 ................................................. 45

x

Figure 2-19. Expected mechanism of response of 2-23 to base .............................................. 45

Figure 2-20. Response of reagent 2-23 to 1 equiv of piperidine ............................................. 46

Figure 2-21. NMR spectra of the degradation of 2-23 after exposure to piperidine ............... 47

Figure 2-22. Kinetics comparison of 2-23 and control reagent 2-24 ...................................... 47

Figure 2-23. Kinetics of the decomposition of 2-23 in solution ............................................. 48

Figure 2-24. NMR spectra of the decomposition of 2-23 in solution .................................... 49

Figure 2-25. Proposed mechanism for the autooxidation of 2-23 ........................................... 49

Figure 2-26. Proposed Diels-Alder reaction between 2-23 and 2-27 ...................................... 50

Figure 2-27. Synthetic scheme for furan monomer 2-33 ........................................................ 50

Figure 2-28. Proposed mechanisms of resonance in 2-furylcarbamates ................................. 51

Figure 2-29. Strategies for increasing the stability of 2-furylcarbamates ............................... 51

Figure 2-30. Synthetic scheme for thiophene model reagent 2-39 ......................................... 52

Figure 2-31. Kinetics and NMR data: exposure of 2-39 to a 10% piperidine solution ........... 53

Figure 2-32. Kinetics comparison of 2-39 and control reagent 2-40 ...................................... 54

Figure 2-33. Synthetic scheme for thiophene monomer 2-47 ................................................. 55

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Chapter 3

Figure 3-1. Depolymerization mechanism of poly(benzyl ethers) containing a single

reaction-based detection unit at the terminus of the polymer ............................... 64

Figure 3-2. Depolymerization mechanism of poly(benzyl ethers) with reaction-based

detection units on each monomer unit .................................................................. 65

Figure 3-3. Structures of polymers 3-1, 3-2, and 3-3 by Yeung ............................................. 65

Figure 3-4. Photographs of solid-state studies exposing 3-1 to TBAF by Yeung ................... 66



Figure 3-7. Poly(phthalaldehyde) polymers with end caps of differing polarity .................... 68

Figure 3-8. Structures of Pd(0)-responsive poly(benzyl ethers) with varying degrees of

polarity on each repeating unit of the polymer ..................................................... 69

Figure 3-9. Synthetic scheme for monomer 3-7 ...................................................................... 70

Figure 3-10. Synthetic scheme for monomer 3-8 .................................................................... 70


Figure 3-12. Conditions for anionic polymerization of polymers 3-4, 3-5, and 3-18 ............. 71

Figure 3-13. Synthesis of polymer 3-6 via azide/alkyne cycloaddition .................................. 72

Figure 3-14. Depolymerization reaction and conditions for solution phase studies ............... 73

xii

Figure 3-15. GPC chromatograms of polymers 3-4 and 3-6 in response to Pd(PPh3)4 and

DBU in THF ....................................................................................................... 73

Figure 3-16. GPC chromatograms of solution phase control studies for 3-4 and 3-6 ............. 74

Figure 3-17. Time lapsed photographs of the solid-state depolymerization of discs

prepared from polymers 3-4, 3-5, and 3-6 .......................................................... 75

Figure 3-18. Photographs of solid-state control studies of 3-4, and 3-6 ................................. 76

Figure 3-19. GPC chromatograms of the solution surrounding solid-state control studies

of polymers 3-4 and 3-6 ...................................................................................... 77

Figure 3-20. GPC analysis of the solution surrounding a solid-state depolymerization

experiment with polymer 3-6 .............................................................................. 78

Figure 3-21. LCMS analysis of the solution surrounding a solid-state depolymerization

experiment with polymer 3-6 .............................................................................. 78

Figure 3-22. Contact angle measurements of polymer films of 3-4, 3-5, and 3-6 ................. 79

Figure 3-23. SEM images of discs fabricated from 3-4, 3-5, and 3-6 ..................................... 80

Figure 3-24. Young’s modulus measurements of polymers 3-4, 3-5, and 3-6 ........................ 81

xiii

Chapter 4

Figure 4-1. Mechanophores used to create mechanoresponsive polymers ............................. 85

Figure 4-2. Illustration of the mechanism of polymer chain scission in response to

ultrasound sonication ............................................................................................ 86

Figure 4-3. Proposed mechanims for the heterolytic cleavage of poly(ethylene glycol) in

water by Aktah and Frank .................................................................................... 88

Figure 4-4. Proposed mechanism of heterolytic cleavage using a triarylsulfonium salt

mechanophore by Moore ...................................................................................... 88

Figure 4-5. Proposed mechanism for heterolytic cleavage and subsequent

depolymerization of poly(phthalaldehyde) by Moore and Boydston ................... 89

Figure 4-6. Trapping experiment data of poly(phthalaldehyde) by Moore ............................. 90

Figure 4-7. Synthetic schemes for polymers 4-1, 4-2, and 4-3 ............................................... 91

Figure 4-8. Setup of the sonication apparatus ......................................................................... 92

Figure 4-9. Response of 4-1 (45.4 kDa, DP = 224) to ultrasound sonication ......................... 93

Figure 4-10. NMR spectra of 4-4 production following sonication of 4-1 ............................. 94

Figure 4-11. Response of 4-2 (44.2 kDa, DP = 151) to ultrasound sonication ....................... 95



Figure 4-14. Trapping experiment of 4-1 (59.0 kDa, DP = 290) with 2-methylindole ........... 98

xiv

Figure 4-15. Trapping experiment of 4-1 (59.0 kDa, DP = 290) with TBC-Cl/pyridine ........ 99

Figure 4-16. Comparison of 4-1 end group trapping efficiency ............................................ 99

Figure 4-17. Trappping experiment of 4-2 (44.2 kDa, DP = 151) with 2-methylindole ......... 100

Figure 4-18. Responses of varying lengths of 4-1 to ultrasound sonication ........................... 101

Figure 4-19. Graphs depicting the production of 4-4 in response to ultrasound sonication

of multiple lengths of 4-1 ................................................................................... 102

Figure 4-20. Schematic illustration of terminating depolymerization of 4-1 through back-

biting cyclization ................................................................................................ 103

xv

Chapter 5

Figure 5-1. Synthetic scheme for compound 1-25 .................................................................. 112








Figure 5-9. Synthetic scheme for monomer 3-7 ...................................................................... 137


Figure 5-11. Synthetic scheme for compound 3-16 ................................................................ 140


Figure 5-13. Synthetic scheme for compound 3-22 ................................................................ 143

Figure 5-14. Synthetic scheme for polymer 3-4 ...................................................................... 144


Figure 5-16. Synthetic scheme for polymer 3-18 .................................................................... 147


xvi

ACKNOWLEDGEMENTS

I would have never made it this far without the unwavering support and love I’ve

received from my mother, Janet, and my father, Tim, to whom I dedicate this thesis. From the

classroom to the baseball field, they always provided everything I needed to succeed throughout

my entire life. Additionally, to my grandmother, Karen, and her father, Nis, for paving the way

and setting high standards for producing chemists in our family.

To my advisor, Scott Phillips, for giving me every opportunity I needed to develop into a

true scientist. He helped to cultivate my intellectual curiosity and instilled the confidence I

needed to work independently through scientific challenges. His drive and creativity will leave a

lasting impression on my career as a scientist and as a professional. I would also like to thank

committee members Ken Feldman, Rob Rioux, Alex Radosevich, and especially Pshemak

Maslak, who pinch-hit in a crucial moment when scheduling conflicts arose for my defense.

Phillips Group members, past and present, have been an astounding collection of

intelligent, passionate, and hard-working scientists. I could not have asked for better mentors

early on in my graduate school than Kyle Schmid, Hemakesh Mohapatra, and Kimy Yeung, who

constantly helped instill in me the standards of conducting high-quality research. Furthermore, to

Anthony DiLauro and Mike Olah, who provided invaluable guidance in my transition to

becoming a polymer chemist. Finally, to Adam Brooks, who I’ve literally spent more time with

over the past four years than anyone else, for being a great friend and coworker who I could

always count on to have thoughtful, detailed conversations about chemistry.

To my roommates, Sean, and Mark, as well as our good friends from Founders, Oskar

Blues, Tröegs, and Ommegang, for always being the outlet I needed to escape the rigors of grad

xvii

school. As well as my friends Brittney, Ryan, Nick, Matt, Steve, Brian, Erica, and Ina, who

helped me to create a wealth of memories during my five years in State College. Additionally to

the inventors of streaming online radio, who allowed me to keep up with the Huskers, Cyclones,

Bluejays, Royals, Angels, and Chiefs during countless late night spent in the lab.

And last, but not least, to my girlfriend Jenny, who has been the most constant source of

inspiration, motivation, and support throughout my graduate school career. I cannot even begin to

describe how valuable it has been to have someone that has been through this gauntlet before to

help guide and encourage me every step of the way. I am so excited to move to Cincinnati to

begin a new chapter in our lives together.

1

Chapter 1

Base-Mediated Autocatalytic Signal Amplification

1.1 Introduction

There is an increasing demand for inexpensive, stable, and easy-to-use diagnostic

tests.1 Current efforts are focused on creating assays that do not require the use of

instrumentation, since electricity often is not accessible in resource-limited environments.

In the absence of instrumentation, low intensity readouts and high limits of detection are

common drawbacks of traditional point-of-use assays.2 Thus, steps are currently being

taken to overcome these limitations, including the development of small molecule

reagents for signal amplification.3–8

The ideal reagent would be thermally stable in all environmental conditions and

provide a readout that is visible to the naked eye in response to only trace quantities of a

desired analyte. In order for the reagent to be practical in a point-of-use assay, it must

amplify a signal rapidly in response to concentrations of the analyte that are below

biologically-relevant thresholds. An attractive approach to this challenge is to develop a

reagent that is capable of amplifying a signal autonomously only after exposure to a trace

level of a specific stimulus.

2

1.2 Catalytic Amplification Systems

Catalytic amplification is a process in which a single molecule is responsible for

converting multiple copies of the same substrate into a desired product. As the reaction

progresses, the amount of product will increase proportionally as long as catalyst

turnover does not diminish. This is an appealing strategy toward creating signal

amplification reagents for diagnostic assays. Amplification systems have been developed

using two predominant classes of catalytic amplification: i) transition metal catalysis and

ii) enzyme-based catalysis.

1.2.1 Transition Metal Catalytic Amplification

Transition metal catalysts are commonly employed as a method for performing

complex chemical transformations while using small amounts of expensive metal

reagents. While known predominantly for their use in synthetic chemistry, transition

metal catalysts have been adapted for use in signal amplification reactions due to their

ability to execute the same reaction on multiple equivalents of a substrate. As long as the

catalyst continues to convert reactants to products (i.e. the catalyst is not poisoned or

degraded), signal amplification is achieved until the substrate is consumed (Figure 1-1).

Figure 1-1. Schematic depiction of catalytic signal amplification.

3

In 2004, Anslyn and coworkers developed one of the first examples of transition

metal catalysis for signal amplification.9 Activation of this system occurs in response to

Cu(II), which preferentially displaces an inactive Pd(II) catalyst from a polyazacyclam

inhibitor (Figure 1-2). Once the palladium species is activated by release, it catalyzes an

intramolecular Heck cross-coupling reaction of 1-1, which amplifies the signal by

forming highly fluorescent indole 1-2 as a readout. This signal amplification reaction is

capable of detecting Cu(II) concentrations as low as 30 nM over the course of 1.5 h.

Figure 1-2. Catalytic signal amplification based on Cu(II) detection and a subsequent

Heck cross-coupling reaction to produce an amplified fluorescent produc.9 Reproduced

with permission from J. Am. Chem. Soc. 2004, 126 (45), 14682−14683. Copyright 2004

American Chemical Society.

A second approach to stimulus-induced activation of a transition metal catalyst

was reported by Mirkin and coworkers.10

This allosterically-regulated system is based on

the activation of a zinc catalyst at the center of a macrocyclic compound (Figure 1-3).

The initial structure of macrocycle 1-3 is compressed, and the zinc catalyst is sterically

hindered due to the bulky surrounding ligands. The catalyst is consequently incapable of

reacting with the amplification substrate (1-4). However, two tetravalent rhodium atoms

4

within the macrocycle change geometry in the presence of Cl− and CO, which

subsequently expands the macrocycle and exposes the interior of the zinc catalysts

(compound 1-5). Following activation, the zinc atoms perform catalytic cleavage of the

phosphate group on 2-(hydroxypropyl)-p-nitrophenyl phosphate (1-4). Reaction progress

can be monitored with UV/Vis spectroscopy, measuring the generation of yellow 4-

nitrophenol (1-6), the amplified reaction product.

Figure 1-3. Allosterically-regulated catalytic signal amplification as demonstrated by

Mirkin and coworkers.10

Activation of macrocycle 1-3 leads to catalytic amplification of

the chemical reporter, 4-nitrophenol (1-6). Reproduced with permission from J. Am.

Chem. Soc. 2007, 129 (46), 14182−14183. Copyright 2007 American Chemical Society.

5

1.2.2 Enzyme-Based Amplification

Enzyme-based amplification works in a similar capacity to transition metal-

catalyzed amplification, but does not require a preliminary step to activate the enzyme for

catalysis. Instead, the enzymes are predisposed to perform substrate-specific reactions.

Enzymes typically contain one or more active sites, which are regions capable of

selectively binding a substrate, performing a particular chemical transformation, and then

releasing the products to make the active site available for another substrate.

For example, β-galactosidase is a hydrolase enzyme that catalyzes the hydrolysis

of β-galactosides into monosaccharides through cleavage of a glycosidic bond.11

Rotello

and coworkers demonstrated a signal amplification system predicated on the cleavage of

a galactose unit from 4-methylumbelliferyl-β-D-galactopyranoside (1-7) to catalytically

amplify highly fluorescent 4-methylumbelliferone12

(1-8, Figure 1-4). The reaction rate is

dose-dependent, as the production of 1-8 can be monitored and used to calculate the

amount of β-galactosidase in a given sample.

Figure 1-4. Enzymatic signal amplification using β-galactosidase to facilitate the

production of a fluorescent coumarin derivative (1-8).12

6

Rates of amplification in enzymatic catalysis reactions can be correlated to the

concentration of β-galactosidase in solution, providing a versatile strategy for detecting

the presence of the enzyme in a given sample. Other systems have been developed in a

similar manner to create diagnostic reactions for enzymes such as alkaline phosphatase

and horseradish peroxidase.13

1.2.3 Summary of Catalytic Amplification

While catalysis is a versatile approach to signal amplification, many assays still

fall short of the requirements necessary for viable point-of-need diagnostics. Assays

containing biological molecules (i.e., enzymes or proteins) are often not thermally stable,

and thus decrease in activity when stored a ove 0 C. Additionally, since there is a fixed

concentration of the catalyst (e.g., Pd(0)), these methods often are not sensitive enough to

enable rapid trace-level detection of contaminants or biomarkers for disease. Overcoming

this limitation requires the development of more sensitive reaction systems that amplify

the reaction stimulus itself while simultaneously providing a visible readout.

1.3 Autocatalytic Amplification

1.3.1 Introduction to Autocatalysis

Autocatalysis is a unique type of amplification in which the product of a reaction

is capable of catalyzing the formation of more of itself.14

It may be argued that

autocatalysis is the most efficient method for signal amplification, as the amount of

chemical signal is amplified exponentially while never itself being consumed. As a result,

7

an autocatalytic reaction displays sigmoidal kinetics. The initial step in an autocatalytic

process is activation of a catalyst, which in turn exponentially amplifies the concentration

of the initiating species in the reaction. (Figure 1-5).15

Figure 1-5. Schematic illustration of an autocatalytic signal amplification reaction.

While many naturally-occurring autocatalytic systems exist, there are relatively

few examples of small molecule autocatalytic amplification.1,14,16–19

One well-known

autocatalytic process is the “vinegar syndrome,” in which acid-sensitive cellulose acetate

films produce acetic acid upon degradation, which further amplifies the rate of hydrolysis

of the acetal functionality in cellulose.20

This mechanism is also responsible for the

autocatalytic degradation of acetylsalicylic acid (aspirin). Additionally, autocatalysis can

occur during i) silver reduction21

(where the reduction of Ag(I) to Ag(0) is catalyzed by

Ag(0)), ii) formation of tin pest22

(the transformation of β-tin to α-tin), and iii) the

Belousov-Zhabotinsky (BZ) reaction23

(an oscillating reaction catalyzed by metal-ion

oxidation and the bromination of malonic acid by bromates).

8

1.3.2 Examples of Autocatalysis

A landmark advancement in small molecule autocatalysis was published by

Mirkin and coworkers in 2008 by modifying the previously discussed allosteric zinc

catalysis reaction7 (Figure 1-3). Instead of using Cl

− and CO as activating reagents, the

revised system employs an acetate ion as the initiator for selective opening of the

macrocyclic cage. Once activated, the available zinc atoms catalyze the cleavage of acetic

anhydride, which produces an additional equivalent of the acetate initiator (Figure 1-6). A

pH-sensitive colorimetric dye was included in the mixture to report the increase in acidity

of the reaction medium following autocatalytic production of acetic acid.

Figure 1-6. Schematic depiction of the autocatalytic reaction performed by the enzyme

mimic system developed by Mirkin and coworkers.7

Ultimately, autocatalytic chemical reactions are rare, the majority of which are

not suitable for use in diagnostics or point-of-need assays. As a starting point for

addressing this challenge, our group adapted a non-linear reaction previously identified

by Ichimura and coworkers24

(Figure 1-7). Following an initial detection event of an

amine base by deprotonation of Fmoc, the system exponentially amplifies the

9

concentration of aliphatic amines through carbamate elimination and subsequent

regeneration of the initial amine.

Figure 1-7. Autocatalytic fragmentation of 1-9 developed by Ichimura and coworkers.24

Ichimura used the base proliferation reaction for photolithography (Figure 1-8),24–

26 where exposure of photo-sensitive compound 1-10 to light leads to the release of a

diamine. The diamine catalytically deprotonates the fluorenylmethyloxycarbonyl (Fmoc)

groups on compound 1-11. Deprotection of 1-11 subsequently releases 1,6-

hexanediamine, which is used as a crosslinking reagent for epoxide polymer 1-12.

Figure 1-8. Base-mediated autocatalysis as a method for photo-induced crosslinking to

create chemically-amplified photoresists.25

Reproduced with permission from J. Mater.

Chem. 2004, 14 (3), 336−343. Copyright 2004 Royal Society of Chemistry.

10

Mohapatra and Phillips later applied this autocatalytic reaction toward the

development of 1-13, the first autocatalytic signal amplification reagent for use in point-

of-need assays (Figure 1-9a).8 Included in the output of each reaction cycle is a

dibenzofulvene chromophore, which can be quantified easily throughout the reaction by

UV/Vis spectroscopy. When used as a signal amplification reagent, 1-13 is capable of

detecting trace levels of piperidine (.001 equiv) over the course of 18 h (Figure 1-9b).

Figure 1-9. a) Fmoc carbamate-based autocatalytic amplification. b) Response profiles of

the reaction when exposed to piperidine.8 Reproduced with permission from Chem.

Commun. 2012, 48 (24), 3018−3020. Copyright 2012 Royal Society of Chemistry

a)

b)

11

Additionally, Mohapatra and Phillips adapted the same signal amplification

mechanism toward the detection of multiple analytes8 (Figure 1-10). Their approach

creates an avenue for tailoring diagnostics to detect numerous analytes using the same

underlying mechanism of autocatalytic signal amplification. For example, by replacing

Fmoc with an allyloxycarbonyl (Alloc) group, piperidine can be released from activity-

based detection reagent 1-14 in the presence of Pd(0). If piperidine-sensitive signal

amplification reagent 1-13 is included in the same solution, the concentration of

piperidine will be amplified in response to Pd(0) (Figure 1-10). This particular tandem

amplification system has a limit of detection of 12 ppm Pd(0), which is near the

government-regulated threshold for the concentration of palladium in drugs (5−10 ppm).8

Figure 1-10. A reagent (1-14) designed for a tandem system to detect palladium (0), and

subsequently amplify the signal via base-mediated autocatalysis using reagent 1-13.8

Reproduced with permission from Chem. Commun. 2012, 48 (24), 3018−3020. Copyright

2012 Royal Society of Chemistry

12

1.3.3 Limitations of Amplification Reagent 1-13

While this autocatalytic system successfully detects trace quantities of analytes,

the rate of the core signal amplification reaction in this system is far slower than is

desirable for use in practical point-of-need assays. This is primarily a result of the slow

initial induction period. Thus, we conducted research on a series of reagents with the goal

of reducing the time necessary to achieve amplified responses in a base-mediated

amplification reaction.

1.4 Experimental Design

To improve the rate of base-mediated signal amplification, we investigated the

extent to which two physical properties affect the rate of the autocatalytic reaction: i) the

proximity of reactive units to each other, and ii) the presence of a high local effective

concentration of base. By tethering multiple reactive carbamates to a single structure, the

distance a released molecule of piperidine must travel to react with a neighboring Fmoc

carbamate is decreased compared to a solution consisting solely of reagents with a single

reactive moiety (Figure 1-11). As more reactive carbamates are added to a single

molecule, the process of amplification may produce a transient area of high effective

signal concentration near the reagent, perhaps accelerating the rate of the autocatalytic

reaction.

13

Figure 1-11. Schematic depiction of the functional group proximity hypothesis. By

tethering multiple reactive groups to a single molecule (left), a higher density of reactive

groups exists within the same volume of solution.

As a proof of concept for this hypothesis, a series of small molecule reagents (1-

15, 1-16, and 1-17) were synthesized with one, two, and three reactive carbamates,

respectively (Figure 1-12). The benzyl carbamate spacer was removed from the

previously-studied reagent to prevent possible side reactions with the electrophilic

azaquinone methide byproduct or subsequent amine adducts. The removal of the spacer

will also, in theory, accelerate the release of piperidine by providing direct elimination of

carbon dioxide and the amine following a detection event (Figure 1-13). In agreement

with our hypothesis, kinetics experiments showed that attaching additional carbamates to

a single molecule increases the rate of reaction. We studied the reagents in detail to

further understand these effects.

14

Figure 1-12. Three test reagents designed to determine how additional reactive

carbamates on a single molecule affect the rate of signal amplification in response to

piperidine.

Figure 1-13. Revised reaction mechanism for base-mediated autocatalytic signal

amplification.

15

1.5 Results and Discussion

1.5.1 Synthesis of the Reagents

Model compounds (1-15, 1-16, 1-17) were synthesized from the same core

compound (1-25) containing the autocatalytic Fmoc piperidine carbamate. Compound 1-

25 was synthesized in seven steps with a 22% overall yield by following procedures

partially adapted from Mutter and Bellof27

(Figure 1-14). Due to the reactive nature of the

9-position on the fluorene ring, care was taken to minimize exposure to heat, air, and base

to prevent spurious oxidation, release of piperidine, and premature initiation of the

autocatalytic process.

Figure 1-14. Synthetic scheme for key reagent 1-25.

16

Following the synthesis of 1-25, the appropriate isocyanate linker was coupled to

the free alcohol to produce 1-15, 1-16, and 1-17, also referred to as the monomer, dimer,

and trimer, respectively (Figure 1-15).

Figure 1-15. Coupling reactions used to synthesize 1-15, 1-16, and 1-17 from 1-25.

1.5.2 LCMS Mechanistic Studies

In order to corroborate the expected reaction mechanism, liquid chromatography

mass spectrometry (LCMS) studies were performed to identify each product during the

autocatalytic reaction. In separate experiments, 100 mM solutions of each reagent (i.e., 1-

15, 1-16, or 1-17) was exposed to 0.1 equivalents of piperidine. Aliquots of 2 μL were

removed from the reaction mixture, diluted in 250 μL THF, and then injected into the

LCMS at 60 min intervals. Peaks corresponding to each expected intermediate in the

autocatalytic reactions of 1-16 and 1-17 revealed that the signal amplification reactions

proceeded as desired (Figures 1-16, 1-17 and 1-18 show an example for reagent 1-17).

17

Figure 1-16. Expected products and mass values for the reaction of 1-17 with piperidine.

Figure 1-17. LCMS traces of the autocatalytic reaction of 1-17 at hour intervals,

measured at 254 nm. Reagent 1-17 is represented by the peak ~3.5 min, and each

successive reaction product (Figure 1-16) has an increasingly lower retention time.

Naphthalene (~1.5 min) was used as an internal standard.

M+ H+ = 1553.7 M + H+ = 1424.6

M + H+ = 1295.5 M + H+ = 1166.4

1-17 1-26

1-27 1-28

0 1 2 3 4 5Retention Time (min)

1 h

2 h

3 h

4 h

5 h

6 h

7 h

18

Figure 1-18. Plot of LCMS data indicating relative concentrations of each reaction

species throughout the course of the autocatalytic reaction of 1-17. Colors correspond to

reagents in Figure 1-16: 1-17 (black), 1-26 (blue), 1-27 (orange), 1-28 (green).

1.5.3 UV/Vis Kinetic Studies

A series of UV/Vis experiments were then designed to measure the rates of

reaction for each model compound. Each reagent (100 mM in THF) was exposed to 0.1

equivalents of piperidine. Every hour, 1 μL of the solution was removed and diluted in 1

mL THF, and the absorbance was analyzed via UV/Vis spectroscopy (Figure 1-19).

Formation of dibenzofulvene following elimination of carbon dioxide generates a new

peak maximum at 310 nm. The increase in absorbance at this wavelength was used to

generate the kinetics graph in Figure 1-20.

1 2 3 4 5 6 7

LCM

S In

tegr

atio

n(r

ela

tive

to n

aph

thal

en

e)

Time (h)

19

Figure 1-19. Time lapsed UV/Vis data of dibenzofulvene formation following the

reaction of 1-15 with 0.1 equiv piperidine.

Figure 1-20. Reaction rate comparison of autocatalytic reagents 1-15, 1-16, and 1-17 in

THF in response to 0.1 equiv piperidine. The data points are the average of three

measurements, and the error bars reflect the standard deviation of these averages.

290 300 310 320 330

Ab

sorb

ance

Wavelength (nm)

t = 0

t = 18 h

0 2 4 6 8 10 12 14

(A −

Ao)/

(Am

ax−

Ao)

Time (h)

1-15, 1-16, 1-17

20

While incorporating more reactive functional groups per molecule increases the

rate of reaction, the duration of the reaction (time necessary for the reaction to reach 80%

completion) does not decrease proportionally with the addition of each carbamate (i.e.,

the duration of reaction for the dimer was not half of the duration of reaction for the

monomer) (Figure 1-21a). This non-proportional relationship also holds true for the rate

of dibenzofulvene production for all three reagents. By plotting dibenzofulvene

concentration against time, the slope of the data at any given point within the kinetics

profile expresses the instantaneous rate of change in dibenzofulvene concentration. The

largest rate of dibenzofulvene production found in the reactions of 1-15, 1-16, and 1-17

with 0.1 equiv piperidine is illustrated in Figure 1-21b.

Figure 1-21. a) Time required to reach 80% completion for the autocatalytic reactions of

reagents 1-15, 1-16, and 1-17 (100 mM in THF) after exposure to 0.1 equiv piperidine

(Figure 1-20). b) Maximum rate of change of dibenzofulvene concentration in the

reaction described in a) for reagents 1-15, 1-16, and 1-17.

1-15 1-16 1-171-15 1-16 1-17

7.47 h

4.71 h

3.56 h16.2 M/h

25.5 M/h

31.8 M/ha) b)

21

We hypothesized that, due to the increased planarity of dibenzofulvene, it is

possible that a structural conformation change following the first detection event on the

dimer or trimer may inhibit future piperidine units from accessing remaining carbamates

on the molecule. To test this theory, intermediates of each autocatalytic reagent (Figure

1-22) were isolated by column chromatography and used for individual kinetics

experiments. If the conformation hypothesis is correct, 1-15 and 1-26 should exhibit

different kinetics profiles. In this case, we could expect the rate of the dimer intermediate

to be visibly slower than the rate of the monomer. The results of these kinetics studies are

shown in Figure 1-23.

Figure 1-22. Autocatalytic reagents and intermediates containing a) a single reactive

Fmoc carbamate and b) two reactive Fmoc carbamates.

a)

b)

22

Figure 1-23. Kinetics profiles of each reagent/intermediate containing a) one remaining

reactive Fmoc carbamate and b) two remaining reactive carbamates in response to 0.1

equiv piperidine in THF.

0 2 4 6 8 10 12

(A −

Ao)

/(A

max

− A

o)

Time (h)

1-15, 1-29 , 1-27a)

0 1 2 3 4 5 6 7 8

(A −

Ao)/

(Am

ax−

Ao)

Time (h)

1-16, 1-26b)

23

The latter UV/Vis experiments reveal that any conformational effects occurring

as a result of prior carbamate elimination reactions have no effect on the subsequent rates

of reaction for each reagent.

1.6 Conclusions

In conclusion, we have shown that the rate of a base-mediated autocatalytic

reaction can be increased by attaching multiple reactive functionalities onto a single

molecule. However, the rates and durations of the reactions do not change proportionally

to the number of Fmoc carbamates added to the structure. On reagents containing more

than one reactive functionality, it was determined that changes in structure or

conformation resulting from prior detection events do not affect succeeding rates of

reaction. These results have provided guidance for potentially incorporating a base-

mediated autocatalytic reaction into a stimuli-responsive material.

24

1.7 References

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2011, 40 (9), 4488–4505.

(2) Yager, P.; Edwards, T.; Fu, E.; Helton, K.; Nelson, K.; Tam, M. R.; Weigl, B. H.

Microfluidic Diagnostic Technologies for Global Public Health. Nature 2006, 442,

412–418.

(3) Amir, R. J.; Pessah, N.; Shamis, M.; Shabat, D. Self-Immolative Dendrimers.

Angew. Chem. Int. Ed. 2003, 42 (37), 4494–4499.

(4) Zhu, L.; Anslyn, E. V. Signal Amplification by Allosteric Catalysis. Angew. Chem.

Int. Ed. 2006, 45 (8), 1190–1196.

(5) Song, F.; Garner, a L.; Koide, K. Highly Sensitive Fluorescent Sensor for

Palladium Based on the Allyl Oxidative Insertion Mech. J. Am. Chem. Soc. 2007,

129 (41), 12354–12355.

(6) Masar, M. S.; Gianneschi, N. C.; Oliveri, C. G.; Stern, C. L.; Nguyen, S. T.;

Mirkin, C. A. Allosterically Regulated Supramolecular Catalysis of Acyl Transfer

Reactions for Signal Amplification and Detection of Small Molecules. J. Am.

Chem. Soc. 2007, 129 (33), 10149–10158.

(7) Hyo, J. Y.; Mirkin, C. A. PCR-like Cascade Reactions in the Context of an

Allosteric Enzyme Mimic. J. Am. Chem. Soc. 2008, 130 (35), 11590–11591.

(8) Mohapatra, H.; Schmid, K. M.; Phillips, S. T. Design of Small Molecule Reagents

That Enable Signal Amplification via an Autocatalytic, Base-Mediated Cascade

Elimination Reaction. Chem. Commun. 2012, 48 (24), 3018–3020.

(9) Wu, Q.; Anslyn, E. V. Catalytic Signal Amplification Using a Heck Reaction. An

Example in the Fluorescence Sensing of Cu(II). J. Am. Chem. Soc. 2004, 126 (45),

14682–14683.

25

(10) Hyo, J. Y.; Heo, J.; Mirkin, C. A. Allosteric Regulation of Phosphate Diester

Transesterification Based upon a Dinuclear Zinc Catalyst Assembled via the

Weak-Link Approach. J. Am. Chem. Soc. 2007, 129 (46), 14182–14183.

(11) McCarter, J. D.; Withers, S. G. Mechanisms of Enzymatic Glycoside Hydrolysis.

Curr. Opin. Struct. Biol. 1994, 4 (6), 885–892.

(12) Miranda, O. R.; Chen, H. T.; You, C. C.; Mortenson, D. E.; Yang, X. C.; Bunz, U.

H. F.; Rotello, V. M. Enzyme-Amplified Array Sensing of Proteins in Solution and

in Biofluids. J. Am. Chem. Soc. 2010, 132 (14), 5285–5289.

(13) Porstmann, B.; Porstmann, T.; Nugel, E.; Evers, U. Which of the Commonly Used

Marker Enzymes Gives the Best Results in Colorimetric and Fluorimetric Enzyme

Immunoassays: Horseradish Peroxidase, Alkaline Phosphatase or ??-

Galactosidase? J. Immunol. Methods 1985, 79 (1), 27–37.

(14) Bissette, A. J.; Fletcher, S. P. Mechanisms of Autocatalysis. Angew. Chem. Int. Ed.

2013, 52 (19), 12800–12826.

(15) Robertson, A.; Sinclair, A. J.; Philp, D. Minimal Self-Replicating Systems. Chem.

Soc. Rev. 2000, 29 (2), 141–152.

(16) Bachmann, P. A.; Luisi, P. L.; Lang, J. Autocatalytic Self-Replicating Micelles as

Models for Prebiotic Structures. Nature 1992, 357, 57–59.

(17) Blackmond, D. G. Asymmetric Autocatalysis and Its Implications for the Origin of

Homochirality. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (16), 5732–5736.

(18) Gerdts, C. J.; Sharoyan, D. E.; Ismagilov, R. F. A Synthetic Reaction Network:

Chemical Amplification Using Nonequilibrium Autocatalytic Reactions Coupled

in Time. J. Am. Chem. Soc. 2004, 126 (20), 6327–6331.

(19) Meyer, A. J.; Ellefson, J. W.; Ellington, A. D. Abiotic Self-Replication. Acc.

Chem. Res. 2012, 45 (12), 2097–2105.

26

(20) Allen, N. S.; Edge, M.; Appleyard, J. H.; Jewitt, T. S.; Horie, C. V.; Francis, D.

Degradation of Historic Cellulose Triacetate Cinematographic Film: The Vinegar

Syndrome. Polym. Degrad. Stab. 1987, 19 (4), 379–387.

(21) Newman, G. R.; Jasani, B. Silver Development in Microscopy and Bioanalysis: A

New Versatile Formulation for Modern Needs. Histochem. J. 1998, 30 (9), 635–

645.

(22) Plumbridge, W. J. Tin Pest Issues in Lead-Free Electronic Solders. J.Mat. Sci.

Mater. Electron. 2007, 18, 307–318.

(23) Sirimungkala, A.; Försterling, H.-D.; Dlask, V.; Field, R. J. Bromination Reactions

Important in the Mechanism of the Belousov−Zha otinsky System. J. Phys. Chem.

A 1999, 103 (8), 1038–1043.

(24) Arimitsu, K.; Miyamoto, M.; Ichimura, K. Applications of a Nonlinear Organic

Reaction of Carbamates to Proliferate Aliphatic Amines. Angew. Chem. Int. Ed.

2000, 39 (19), 3425–3428.

(25) Arimitsu, K.; Ichimura, K. Nonlinear Organic Reaction of 9-Fluorenylmethyl

Carbamates as Base Amplifiers to Proliferate Aliphatic Amines and Their

Application to a Novel Photopolymer System. J. Mater. Chem. 2004, 14 (3), 336–

343.

(26) Igarashi, A.; Arimitsu, K.; Seki, T.; Ichimura, K. Novel Base-Sensitive Polymers

Generating Amino Groups from Their Side Chains in a Nonlinear Manner and

Their Application to Photoimaging Materials. J. Mater. Chem. 2008, 18 (5), 560–

566.

(27) Mutter, M.; Bellof, D. A New Base-Labile Anchoring Group for Polymer-

Supported Peptide Synthesis. Helv. Chim. Acta 1984, 67, 2009–2016.

27

Chapter 2

Head-to-Tail Depolymerizable Polymers

2.1 Introduction to Depolymerizable Polymers

In addition to small molecule systems, stimuli-responsive polymers are an

attractive, versatile approach for realizing reaction-based signal amplification.1–3

These

polymers have been designed to change their surface properties,4,5

shape,6,7

or color8 in

response to a specific external stimulus. The response is typically a result of structural

changes to the polymer, which range from intermolecular interactions, reversible

dynamic bond formation, cross-linking, or depolymerization.

Depolymerization can be generally defined as the conversion of a polymeric

material to smaller species in the presence of chemical, physical, or thermal stimuli. This

loose interpretation often is used in the literature to describe a variety of polymer

degradation processes that occur through different means with vastly different outcomes.

Compared to traditional responsive polymers, certain types of depolymerizable polymers

are capable of producing amplified responses as a result of a single detection event. As

the field of depolymerizable polymers continues to advance, new polymers are needed

that are i) easily prepared, with control over molecular weights and polydispersity; ii)

easily outfitted with reaction-based detection groups; iii) stable to acid, base, and heat;

and iv) capable of depolymerizing rapidly and completely in both high and low polarity

environments.

28

2.1.1 Classification of Depolymerization Mechanisms

There are four general categories of depolymerizable polymers, which are

classified by two defining characteristics: i) whether the polymers depolymerize via

repetitive, continuous fragmentation or completely following a single detection event and

ii) whether the initiating signal can be detected selectivity9 (Figure 2-1).

Figure 2-1. Classes of depolymerizable polymers. a) fragmentation depolymerization

following random scission of the polymer backbone (FDb), b) continuous

depolymerization following random scission of the polymer backbone (CDb), c)

fragmentation depolymerization upon cleavage of a reaction-based detection unit (FDr),

d) continuous depolymerization upon cleavage of a reaction-based detection unit (CDr).9

c) FDr

b) CDb

a) FDb

d) CDr

29

All depolymerizable polymers can be separated into one of two classes based on

the mechanism of depolymerization. Fragmentation depolymerization polymers (FD)

simply produce two smaller polymer chains following the initial bond cleavage event,

and do not offer any amplification of the signal. In order for the resulting polymer

fragments to break down further, they must react with additional equivalents of the

desired stimulus. Once the stimulus is either consumed or removed from the system, the

polymer is incapable of depolymerizing further. Alternatively, continuous

depolymerization polymers (CD) produce an electron cascade that can propagate through

the polymer backbone, unzipping the polymer from the point of reaction to the terminus

of the polymer. This electron cascade continuously releases small molecule products

from the polymer chain, providing significant signal amplification as a result of a single

reaction-based detection event. The overall magnitude of signal amplification from the

detection event will increase proportionally to the length of the polymer chain. In this

case, the depolymerization process will continue even if the initiating stimulus is

removed.

Each of the polymers described above can be further classified depending on the

mechanism by which depolymerization is initiated: those that occur following random

bond cleavage in the polymer backbone (b), and those that respond only following the

cleavage of a specific reaction-based detection unit (r). The majority of depolymerizable

polymers fall into category (b), where chain scission occurs at a reactive functionality

within the repeating unit of the polymer backbone. This includes the hydrolysis or

biodegradation of condensation polymers such as polyesters and poly(lactic acid).10

Control over the response of these polymers is limited, as the stimulus cannot be

30

modified and the location at which the stimulus reacts along the polymer chain is

unpredictable.

In contrast, polymers in category (r) contain built-in reaction-based detection

units that provide greater jurisdiction over the specificity of the depolymerization.

Polymers containing these detection groups are designed to respond only in the presence

of a desired stimulus. Since detection units are independent of the polymer backbone, the

reactive groups can be modified to respond in the presence of numerous types of analytes

including light,11

palladium,12

fluoride,13,14

enzymes,15

and multiple, orthogonal stimuli.16

In addition, the location at which the detection event takes place can be manipulated with

specific positioning of reaction-based detection units, which can either be employed as

“end-caps” placed at the terminus of the polymer or as pendant groups along the polymer

backbone.

2.1.2 Continuous, Reaction-Based Depolymerization (CDr)

The greatest degree of amplification is achieved by depolymerizable polymers

that are capable of continuous depolymerization following the cleavage of a reaction-

based detection unit (CDr). A great deal of growth and innovation has occurred in the

field in recent years9,17–19

due to the unique ability of the polymer to provide both

selective and amplified responses. A variety of depolymerizable backbones have been

developed with mechanisms ranging from quinone methide elimination, propagation of a

hemiacetal ion, isocyanate formation, and cyclization. Specific mechanisms and uses of

these polymers are detailed below.

31

2.1.2.1 CDr Poly(carbamates)

Figure 2-2. Schematic depiction of CDr poly(carbamate) depolymerization.

One of the first CDr systems was developed from a previously reported benzyl

carbamate linker used in an innovative platform for the controlled release of a prodrug20

(Figure 2-3). A model release system was developed using reagent 2-1, which was

synthesized containing an enzyme-responsive detection unit, a benzyl carbamate spacer,

and a model drug to demonstrate a stimuli-responsive system for drug activation.

Figure 2-3. a) Scheme depicting the first design of a controlled release carbamate spacer.

b) Model prodrug 2-1 selectively releases 4-nitroaniline in the presence of trypsin.20

a)

b)

32

Release of the model drug occurs following donation of electrons into the ring

from a free amine and subsequent formation of an azaquinone methide intermediate. This

controlled release mechanism was later adapted by Shabat and coworkers21–25

to create

stimuli-responsive dendrimers, which employed quinone methide eliminations and/or

cyclizations to disassemble branched benzyl carbamate systems (Figure 2-4).

Figure 2-4. Dendritic amplification reagent 2-2 developed by Shabat and coworkers.22

Through a series of 1,4-quinone methide eliminations and cyclization events, the

molecule releases eight copies of a model drug in response to a single reaction-based

detection event.

2-2

33

To eliminate the labor-intensive step-wise synthesis of dendritic reaction systems,

Shabat later developed analogous linear polymers through the step growth polymerization

of monomer 2-3. The polymerization was end-capped with 4-hydroxy-2-butanone to

make polymer 2-4, which will respond selectively in the presence of bovine serum

albumin (BSA)26

(Figure 2-5).

Figure 2-5. The lengthy synthesis of dendritic amplifiers was improved with the

synthesis of linear polymer 2-4 through step-wise polymerization of monomer 2-3.26

Ultimately, small polymers consisting of 15 repeating units were used for

depolymerization tests, which were monitored by the increase of aniline products using

fluorescence spectroscopy. The polymer depolymerized completely in approximately 10

h in response to 1 mg/mL BSA in pH 7.4 buffered water, but exhibited significant non-

specific degradation in the absence of the analyte. Numerous challenges have limited the

viability of poly(carbamates) toward many applications, including the inherent instability

of the repeating unit, slow depolymerization times, inefficient synthetic routes, and the

inability to depolymerize in non-polar solvents. Efforts to increase the rate of

poly(carbamate) depolymerization will be discussed later in this chapter.

34

2.1.2.2 CDr Poly(benzyl ethers)

Figure 2-6. Schematic depiction of CDr poly(benzyl ether) depolymerization.

The development of poly(benzyl ethers) as a new class of CDr polymers has

helped to circumvent the numerous limitations of poly(carbamates). The first instance of

using benzyl ethers as a responsive controlled release unit was published in 2003 by

McGrath and coworkers, who used the linkage within a dendritic scaffold.27–30

Benzyl

ether amplification systems depolymerize in a similar manner to poly(carbamates).

Cleavage of the reaction-based detection unit under basic conditions unmasks a

phenoxide anion, which induces an electron cascade and a series of 1,6-quinone methide

eliminations to release the monomeric species (Figure 2-6). McGrath and coworkers

demonstrated the selective depolymerization of a linear enzyl ether oligomer (1−4

repeating units, synthesized in a step-wise fashion) in response to both palladium and UV

light in under two minutes (Figure 2-7).30

However, the longer oligomers failed to

depolymerize to completion, raising additional questions over the ability for poly(benzyl

ethers) to fully depolymerize, especially in low polarity solvents or in the solid state.

Figure 2-7. The selective disassembly of a benzyl ether oligomer.

30

35

Lin and coworkers later demonstrated seminal work resulting in the first

homopolymerization of a poly(benzyl ether) through use of a stable quinone methide

monomer.31

Due to its extremely electrophilic 7-position, quinone methide species are

often too unstable to isolate. However, Lin discovered that adding electron withdrawing

groups to the ring or extending conjugation into a pi system at the 7-position helps

mitigate the molecule’s intrinsic electrophilicity. This strategy provides a more efficient

method for synthesizing poly(benzyl ethers) of higher molecular weights compared to

previous approaches. Olah and coworkers later employed quinone methide anionic

polymerization to synthesize the first stimuli-responsive depolymerizable poly(benzyl

ethers).14

Importantly, this class of CDr polymers has exhibited extensive stability to acid,

base and heat as well as the ability to depolymerize within hours in relatively low polarity

solvents. This was first demonstrated by exposing tert-butylsilyl end-capped polymer 2-7

to tetrabutylammonium fluoride (TBAF) in THF14

(Figure 2-8).

Figure 2-8. a) Synthesis of polymer 2-7 from a stable quinone methide monomer. The

reaction is terminated by end-capping with a silyl ether group. b) Cleavage of the

detection unit and subsequent depolymerization of 2-7 in the presence of TBAF.14

a)

b)

36

Furthermore, the directly reversible procedure of monomer polymer

monomer has produced a novel, and far more efficient, approach to creating a closed-

loop system for the recycling of plastics.32

Development of the poly(benzyl ether)

backbone has also provided a versatile platform for designing a library of stimuli-

responsive depolymerizable polymers with a variety of material properties. This includes

cross-linkable responsive polymers, polymers with adhesive or elastomeric properties,

and polymers capable of depolymerizing in the solid state. Efforts to develop the latter

will be discussed in Chapter 3 of this dissertation.

2.1.2.3 Intramolecular Cyclizing CDr Polymers

Figure 2-9. Schematic depiction of depolymerizable polymers utilizing an alternating

cyclization/quinone methide elimination mechanism.33

A unique approach toward CDr polymers developed by Gillies and coworkers

employs an intramolecular cyclization in tandem with quinone methide formation as a

design for a biodegradable polymer.33

Following cleavage of the reaction-based detection

unit, the unmasked end of an ethylene linker cyclizes to release a free phenol, which then

37

proceeds through 1,6-quinone methide elimination and loss of CO2 to unmask the next

available ethylene linker (Figure 2-9). The Gillies group ultimately developed this design

by drawing from their own previous work,34–36

as well as the work of others.22,37

The first generation design was based on an N,N-ethylenediamine linker (2-8) and

exhibited extremely slow depolymerization kinetics. The polymer depolymerized

completely in ~7 days.34

In order to optimize the rate-limiting cyclization step, Gillies

and coworkers later synthesized polymer 2-9, which replaced the carbamate linker with a

more electrophilic carbonate. The substitution of a single atom in the repeating unit

greatly reduced the time necessary for complete depolymerization of 2-9, which occurred

in less than 7 h.33

Furthermore, Gillies and coworkers synthesized polymer 2-10

containing a 2-thioethanol linker, which increased the nucleophilicity of the cyclizing

species compared to the previously used secondary amine. This second alteration further

accelerates the depolymerization reaction to 5 h.33

However, the delicate balance of

stability vs. reactivity was affected as a result of these transformations, as background

hydrolysis was also found to increase with the inclusion of enhanced nucleophiles and

electrophiles along the polymer backbone. No solid-state depolymerization studies have

been published using cyclizing CDr polymers.

38

2.1.2.4 CDr Poly(Phthalaldehyde)

Figure 2-10. Schematic depiction of poly(phthalaldehyde) depolymerization.

In contrast to poly(carbamates) and poly(benzyl ethers), CDr poly(phthalaldehyde)

is an acetal-based polymer that depolymerizes at an exceptionally fast rate in both

solution and the solid state. Poly(phthalaldehyde) was first synthesized in 1967 by Aso

and Tagami,38

and was further developed in 1983 by Ito and Wilson as a photoacid-

sensitive substrate for lithography resists.39

The acetal linkages in the polymer backbone

are exceedingly sensitive to acidic conditions, which will trigger rapid and complete

depolymerization of the polymer following the cleavage of a single acetal unit anywhere

along the polymer backbone. By end-capping the polymer with a reaction-based detection

unit, Phillips and coworkers developed the first examples of poly(phthalaldehyde) that

satisfy the criteria of CDr polymers.12,13,40–42

Poly(phthalaldehydes) are also unique in that

they are capable of being end-capped on both termini of the polymer chain, providing an

opportunity to functionalize the polymer with two reaction-based detection units selective

for two separate analytes.

The first generation design of poly(phthalaldehyde) was synthesized from

commercially available o-phthalaldehyde, and demonstrated the ability to depolymerize

selectively in the solid-state within a patterned plastic13

(Figure 2-11). Following the

addition of a specific stimulus (i.e. TBAF), the patterned plastic sheet only exhibited

depolymerization in areas containing fluoride-responsive 2-11. In contrast, allyl end-

39

capped polymer 2-12 remained intact following exposure to fluoride. This example led to

future solid-state applications of poly(phthalaldehyde), including responsive coatings for

non-mechanical pumps40,41

and controlled release microcapsules.42

Figure 2-11. A cartoon illustrating selective depolymerization of a plastic patterned with

different stimuli responsive materials. In the presence of TBAF, only the fluoride-

responsive core of the plastic depolymerizes.13

Adapted with permission from J. Am.

Chem. Soc., 2010, 132 (17), 9234−9235. Copyright 2010 American Chemical Society.

2.1.2.5 Depolymerizable Poly(glyoxylates)

Figure 2-12. Schematic depiction of poly(ethyl glyoxylate) depolymerization.

The final class of CDr polymers, poly(glyoxylates), was first developed in 1979

by Monstanto for use in biodegradable detergent formulations.43

Due to its susceptibility

to hydrolysis and low toxicity of the products, poly(glyoxylates) have been an appealing

patterned plastic sheet

Specific stimulus (TBAF)

plastic sheet with altered features

40

polymer for use in biomaterials.44

More recently, poly(glyoxylates) have gained attention

as a new backbone for CDr polymers, which was first reported by Gillies and coworkers

in 2014.45

These acetal-based polymers, which are synthesized in a similar manner to

poly(phthalaldehydes), can reach high molecular weights and can be end-capped with

reaction-based detection units at both termini of the polymer. Notably, the significantly

higher ceiling temperature of poly(ethyl glyoxylate) (Tc = 38 °C)45

compared to

poly(phthalaldehyde) (Tc = −43 °C)46

likely leads to slower depolymerization rates.

Gillies demonstrated the depolymerization of UV-responsive poly(ethyl

glyoxylate) 2-13 (containing a 6-nitroveratryloxycarbonyl (NVOC) end cap) following

exposure to 300-350 nm UV light for 80 min in 9:1 CD3CN−D2O (Figure 2-13).47

Polymer 2-13 exhibited only 70% depolymerization over the course of 24 h, producing

ethyl glyoxylate hydrate (2-14) as the primary observed small molecule product. The

incomplete depolymerization likely is a consequence of the polymer ceiling temperature

being above room temperature. Further studies detailed the solid-state depolymerization

of poly(ethyl glyoxylate), as polymer films made from 2-13 showed complete mass loss

after 17 d in buffered water following 17 h of exposure to UV light.47

These polymers

have also been adapted for use in amphiphilic triblock copolymers for self-assembly into

micellar nanoparticles and subsequent controlled release in aqueous environments.47

Figure 2-13. Depolymerization of NVOC end-capped 2-13 in response to UV light.47

41

2.1.3 Summary of CDr Polymers

CDr polymers are unique macromolecules due to their ability to depolymerize

continuously and completely only in the presence of a specific stimulus. In contrast to

most stimuli-responsive materials, CDr polymers provide large, amplified responses and

can be tailored to respond to a variety of different analytes. However, few examples of

CDr backbones have been reported to date and several challenges must be overcome

before they are suitable for potential commercial applications such as recycling,

controlled release, and analyte detection. CDr polymers must ultimately be easy to

synthesize from cheap commercial chemicals, provide rapid rates of depolymerization,

and be stable during the manufacturing process and daily consumer use.

The ensuing chapters of this dissertation detail efforts to increase the rates of

depolymerization in poly(carbamates) and poly(benzyl ethers). Specifically, we will

discuss the design and synthesis of a novel CDr backbone as well as demonstrate a

strategy for increasing the rate of solid-state depolymerization in predominantly aqueous

environments.

2.2 Efforts to Improve the Rate of Quinone Methide Elimination

Previous studies of poly(carbamate) polymers by Phillips and coworkers have

suggested that azaquinone methide formation is the rate-limiting step of

depolymerization,48–53

especially in low polarity environments. The most notable

limitation to this process is the energetic penalty that must be surmounted to generate the

azaquinone methide intermediate from its more stable aromatic precursor (Figure 2-14).

42

Figure 2-14. Depolymerization mechanism of benzene-based poly(carbamates).

Through a series of physical organic studies to determine the rate of release for a

benzyl carbamate unit, Phillips discovered two techniques for decreasing the HOMO-

LUMO gap between the two species: i) increasing the electron density within the ring49,50

and ii) reducing the aromaticity of the ring in each repeating unit of the polymer.50,51

The

addition of a methyl ether to an oligomeric test reagent provided a 136-fold increase the

rate of release for a single benzyl carbamate unit.50

It was proposed that added electron

density likely increases the molecular orbital interactions between π(ring) and σ*(C-O),

which subsequently lengthens the benzylic C–O bond and facilitates more rapid

azaquinone methide formation. Similarly, by decreasing the aromatic character of the

repeating unit, the energetic penalty that must be paid to form azaquinone methide is also

decreased. This result was demonstrated by Schmid and Phillips by studying the relative

rates of release between a series of aromatic hydrocarbons with differing aromaticities

(Figure 2-15).

43

Figure 2-15. Relative aromaticities and release rates for carbamate spacers with benzene

(2-15), naphthalene (2-16), and phenanthrene (2-17) rings.51

Reproduced with permission

from J. Phys. Org. Chem. 2013, 26 (7), 608−610. Copyright 2013 Wiley & Sons.

Compounds 2-15, 2-16, and 2-17 were exposed to palladium in THF, transferred

to a 1:1 mixture of MeCN and pH 7.1 buffered water, and then injected into an LCMS for

product analysis. The use of phenanthrene-based repeating unit 2-17 (approximately 20%

less aromatic than benzene)54

exhibited a 51-fold increase in rate of release for a single

poly(carbamate) repeating unit.50

Although decreasing aromaticity increases the rate of

release, each compound still requires polar solvents (MeCN and water) to facilitate

quinone methide elimination. This led to the design of a new class of poly(carbamates)

with the goal of imparting the ability to depolymerize in lower polarity solvents.


Based on these previous results, we reasoned that faster depolymerization in

poly(carbamates) might be realized by omitting azaquinone intermediates from the

Test Reagent:

Relative

aromaticity54

t ½ for release

of phenol (min) ~23 h

2-15 2-16 2-17

114

3.7 min

24.9

4.8 min

1.00 0.912 0.813

44

depolymerization mechanism. Thus, we suspected that aromatic rings other than benzene

might give rise to faster depolymerization. Smaller heterocyclic rings, such as furan or

thiophene, have reduced aromatic stabilization, which might allow depolymerization to

occur through lower activation pathways than with benzene (Figure 2-16).

Figure 2-16. Proposed electron cascade and elimination mechanism of furan- or

thiophene-based depolymerizable poly(carbamates).

Furan and thiophene have lower resonance energies than benzene due to reduced

π-delocalization on the heteroatom lone pair. Furthermore, the electronegativity of the

heteroatom influences the extent to which the lone pair participates in cyclic

delocalization. The higher magnitude of electronegativity in oxygen compared to sulfur

results in the notably decreased aromaticity of furan. A summarization of the relative

aromaticity of each ring via resonance energy is located in Figure 2-17.

Figure 2-17. A comparison of resonance energies in benzene, thiophene, and furan.

45


2.4.1 Synthesis and Testing of a Model Furan Repeating Unit

We prepared model compound 2-23 to investigate the viability of using furan as

the repeating unit of a CDr polymer (Figure 2-18). Compound 2-23 was synthesized in 5

steps with a 28% overall yield; the reagent contains the core furan ring, a base-sensitive

Fmoc carbamate as the reaction-based detection unit, and phenol as a reporter molecule.

Exposure of 2-23 to basic conditions ideally will cause an electron cascade through the

furan ring and subsequent release of the pendant reporter molecule (Figure 2-19).

Figure 2-18. Synthetic scheme for model furan reagent 2-23.

Figure 2-19. Expected mechanism of response to base and subsequent release of phenol

from model compound 2-23.

46

To investigate the selective, controlled release of phenol from 2-23, the reagent

was exposed to piperidine (1 equiv.) in CDCl3 and analyzed via NMR by integrating the

furan benzylic peak with respect to tetramethylsilane (TMS). Release of phenol from

reagent 2-23 reached 80% completion in less than 10 h (Figure 2-20a). However, NMR

spectra provide little evidence for the formation of dibenzofulvene, indicating that release

of phenol is not primarily occurring as a result of selective Fmoc deprotection. Free

piperidine is also consumed throughout the course of the reaction (Figure 2-21). LCMS

analysis of the reaction mixture suggests that phenol likely is released through i) an SN2

reaction with piperidine or ii) deprotonation of the carbamate and a subsequent quinone

methide-like electron cascade (Figure 2-20b). This substitution did not take place when

N,N-diisopropylethylamine (DIEA) was used in place of piperidine.

Figure 2-20. a) NMR kinetics for the degradation of compound 2-23 in the presence of 1

equiv. piperidine. b) Proposed reaction in Figure 2-20a (confirmed by LCMS analysis).

0%

20%

40%

60%

80%

100%

0 10 20 30 40

Re

age

nt

Re

mai

nin

g

Reaction Time (h)

a)

b)

47

Figure 2-21. NMR spectra of the degradation of 2-23 in the presence of 1 equiv.

piperidine. The blue rectangle highlights the disappearance of the furan benzylic peak,

and the red rectangles highlight production of free phenol (left) and consumption of

piperidine (right).

In order to verify the proposed mechanisms, we synthesized a second model

compound containing an alloc group (2-24), which is not sensitive to base. NMR and

LCMS experiments reveal that compound 2-24 reacts similarly to 2-23 (Figure 2-22),

indicating that both reagents likely degrade through SN2 or carbamate deprotonation

mechanisms rather than the selective removal of a reaction-based detection unit.

Figure 2-22. Kinetics comparison of compounds 2-23 (blue) and 2-24 (red) following

exposure to 1 equiv. piperidine in CDCl3.

0 h

18 h

0%

20%

40%

60%

80%

100%

0 10 20 30 40 50

Re

age

nt

Re

mai

nin

g

Reaction Time (h)

48

Additional control experiments indicate that 2-furylcarbamates are also

significantly unstable in solution at room temperature. NMR analysis shows nearly

complete disappearance of the furan benzylic peak of 2-23 over the course of 36 hours

under ambient conditions in CDCl3 (Figure 2-23).

Figure 2-23. NMR kinetics of the degradation of 2-23 in CDCl3.

Additionally, the degradation products of compound 2-23 differ from those

generated following the addition of piperidine (Figure 2-24). We hypothesize that 2-23

degrades similarly to the previously reported ring transformation of 2-furylcarbamates to

5-hydroxy-3-pyrrolin-2-ones via autooxidation or photooxidation.55,56

Yakushijin and

coworkers demonstrated that electron-rich 2-furylcarbamates react with molecular

oxygen to create an endoperoxide (2-25) that may further degrade to numerous products

(Figure 2-25). A mass peak corresponding to products 2-26 and 2-27 (M + H+

= 428.1)

was detected following the degradation of 2-23. NMR and LCMS analyses also provided

evidence of the formation of Diels-Alder product 2-28, which is likely formed through

the cyclization of 2-23 with 2-27 (Figure 2-26).

0%

20%

40%

60%

80%

100%

0 10 20 30 40

Re

age

nt

Re

mai

nin

g

Reaction Time (h)

49

Figure 2-24. NMR spectra of the decomposition of 2-23 in CDCl3.

Figure 2-25. Proposed mechanism of the autooxidation of compound 2-23.

0 h

8 h

18 h

50

Figure 2-26. Proposed Diels-Alder reaction occurring between autooxidation product 2-

27 and model compound 2-23.

2.4.2 Synthesis of Furan-based Poly(carbamates)

While model compound 2-23 exhibited significant instability, we proceeded with

attempts to synthesize a furan-based polymer to gauge whether the polymeric structure

provided additional stability to the system. Thus, we synthesized step-wise

polymerization monomer 2-33 in four steps with a 4% overall yield (Figure 2-27).

Figure 2-27. Synthetic scheme for furan monomer 2-33.

2.4.3 Summary of 2-furylcarbamates

Unfortunately, the metastable nature of furan monomer 2-33 frustrated most

attempts to achieve oligomers and/or polymers. The reduced aromaticity in 2-furyl

carbamates limits its ability to stabilize the considerable amount of electron density

51

within the ring. This inherent instability gives rise to decomposition through undesirable

cycloaddition and substitution reactions. We hypothesize that the ring is particularly

susceptible to SN2 reactions due to a partial positive charge at the furan benzylic carbon,

which may lengthen the C−O ond and help facilitate release of phenol (Figure 2-28).

Figure 2-28. Proposed mechanisms of resonance within 2-furylcarbamates that may

elucidate the susceptibility of compound 2-23 toward SN2 reactions.

Based on these results, we have reasoned three approaches toward reducing the

reactivity of 2-furyl carbamates: i) introduce an electron withdrawing group at the 4-

position of the ring; ii) attach an alkyl group at the benzylic position; and iii) change the

heteroatom within the ring (Figure 2-29). These strategies ideally will help to increase

aromaticity and/or reduce electron density within the ring, or increase steric congestion,

thus subsequently discouraging unwanted side reactions.

Figure 2-29. Proposed strategies for increasing the stability of 2-furyl carbamates: i)

addition of an electron withdrawing group on the ring; ii) addition of an alkyl group at the

benzylic position; and iii) introduction of a more aromatic ring structure (thiophene).

52

2.4.4 Synthesis and Testing of a Model Thiophene Repeating Unit

We reasoned that the increased aromaticity of a thiophene ring relative to furan

would eliminate the susceptibility of the reagent toward both SN2 reactions and

autooxidation. To test this hypothesis, we synthesized thiophene model compound 2-39

in 5 steps with a 6% overall yield (Figure 2-30).

Figure 2-30. Synthetic scheme for thiophene model reagent 2-39.

Although compound 2-39 responds slowly to 1 equiv. of piperidine in CDCl3,

NMR analysis illustrates the successful formation of dibenzofulvene. The rate of

selective release of phenol from 2-39 increases significantly under traditional conditions

used for Fmoc deprotection.57

For example, exposure of the reagent to a 10% solution of

piperidine in CDCl3 resulted in complete cleavage of the Fmoc group in 5 h (Figure 2-

31a). However, deprotection of the Fmoc carbamate does not instantaneously result in the

release of phenol. This indicated that either i) the subsequently formed 2-aminofuran

intermediate is relatively stable or ii) the thiophene ring is also susceptible to carbamate

53

deprotonation or an SN2 reaction at the benzylic position. NMR spectra indicate that,

following exposure to a 10% solution of piperidine in CDCl3, release of phenol is 80%

complete in approximately 22 h (Figures 2-31a and 2-31b).

Figure 2-31. a) Data depicting deprotection of Fmoc from 2-39 (blue) and release of

phenol (red) after exposure to 10% piperidine in CDCl3. b) Corresponding NMR spectra.

We then synthesized control reagent 2-40, which released phenol at a similar rate

as 2-39 following exposure to a 10% piperidine solution in CDCl3 (Figure 2-32). This

result indicates that phenol is likely released through a similar non-specific reaction as

a) 2-39 phenol

0 h

3 h

12 h

b)

0%

20%

40%

60%

80%

100%

0 10 20 30 40 50

Re

age

nt

in S

olu

tio

n

Reaction Time (h)

54

proposed with reagent 2-23 and not the desired quinone methide-like elimination.

Although still reactive, the thiophene model reagent degrades and reacts at a far slower

rate than its furan analog. Compound 2-39 also exhibited greater stability in solution than

2-23, as the reagent remained stable over the course of one week. In order for this

structure to be viable for a CDr polymer backbone, future studies will require additional

strategies for increasing the stability of heterocyclic carbamates.

Figure 2-32. Kinetics comparison of compounds 2-39 (blue) and 2-40 (red), monitoring

release of phenol following exposure to 1 equiv. piperidine in CDCl3.

2.4.5 Synthesis of Thiophene-based Poly(carbamates)

To evaluate whether the increased stability of the thiophene model system could

be applied to a depolymerizable polymer, we synthesized monomer 2-47 in 8 steps with a

5% overall yield (Figure 2-33). Several attempts to polymerize 2-47 through step-wise

condensation failed to produce poly(thiophenecarbamates). Typical reaction conditions

consisted of heating 2-47 in the presence of a strong base, resulting in no reaction or

0%

20%

40%

60%

80%

100%

0 10 20 30 40 50 60

Rel

ease

d P

hen

ol

Reaction Time (h)

55

decomposition of the monomer. Further work is required to determine ideal conditions

for the polymerization of a thiophene-based carbamate monomer.

Figure 2-33. Synthetic scheme for thiophene monomer 2-47.

2.5 Conclusion

In conclusion, we have shown that thiophene rings may be viable for use in

synthesizing novel stimuli-responsive poly(carbamates) that may depolymerize in low

polarity environments. In comparison to traditional benzene-based poly(carbamates), the

decreased aromatic character of thiophene may help accelerate formation of the

azaquinone methide derivative, a process that traditionally requires highly polar solvents.

We expect that this work will provide additional insight to design principles for

increasing the depolymerization rate of poly(carbamates). Further research will focus on

the synthesis, characterization, and depolymerization of thiophene-based CDr polymers.

56

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(46) Aso, C.; Tagami, S.; Kunitake, T. Polymerization of Aromatic Aldehydes. II.

Cationic Cyclopolymerization of Phthalaldehyde. J. Polym. Sci. Part A Polym.

Chem. 1969, 7, 497–511.

(47) Fan, B.; Trant, J. F.; Wong, A. D.; Gillies, E. R. Polyglyoxylates: A Versatile

Class of Triggerable Self-Immolative Polymers from Readily Accessible

Monomers. J. Am. Chem. Soc. 2014, 136 (28), 10116–10123.

61

(48) Lewis, G. G.; Ditucci, M. J.; Phillips, S. T. Quantifying Analytes in Paper-Based

Microfluidic Devices without Using External Electronic Readers. Angew. Chem.

Int. Ed. 2012, 51 (51), 12707–12710.

(49) Schmid, K. M.; Jensen, L.; Phillips, S. T. A Self-Immolative Spacer That Enables

Tunable Controlled Release of Phenols under Neutral Conditions. J. Org. Chem.

2012, 77 (9), 4363–4374.

(50) Robbins, J. S.; Schmid, K. M.; Phillips, S. T. Effects of Electronics, Aromaticity,

and Solvent Polarity on the Rate of Azaquinone-Methide-Mediated

Depolymerization of Aromatic Carbamate Oligomers. J. Org. Chem. 2013, 78 (7),

3159–3169.

(51) Schmid, K. M.; Phillips, S. T. Effect of Aromaticity on the Rate of Azaquinone

Methide-Mediated Release of Benzylic Phenols. J. Phys. Org. Chem. 2013, 26 (7),

608–610.

(52) Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Phase-Switching Depolymerizable

Poly(carbamate) Oligomers for Signal Amplification in Quantitative Time-Based

Assays. Macromolecules 2013, 46 (13), 5177–5183.

(53) Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Point-of-Care Assay Platform for

Quantifying Active Enzymes to Femtomolar Levels Using Measurements of Time

as the Readout. Anal. Chem. 2013, 85 (21), 10432–10439.

(54) Randić, M. Aromaticity of Polycyclic Conjugated Hydrocar ons. Chem. Rev.

2003, 103 (9), 3449–3605.

(55) Waldemar, A.; Rodriguez, A. Cyclic Peroxides. 92. Oxygen Atom Transfer by

Furan Endoperoxides. J. Am. Chem. Soc. 1980, 102 (1), 404–406.

(56) Yakushijin, K.; Suzuki, R.; Kawaguchi, N.; Tsuboi, Y.; Furukawa, H. Ring

Transformation of 2-Furylcarbamates to 5-Hydroxy-3-Pyrrolin-2-Ones. Chem.

Pharm. Bull. 1986, 34 (5), 2049–2055.

62

(57) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis: Fifth Edition;

2014.

63

Chapter 3

Solid-State Depolymerization of Poly(benzyl ethers)

3.1 Introduction

The ability to efficiently depolymerize in the solid state could considerably

expand the scope of potential applications for CDr polymers.1 Compared to other current

polymer technologies, the ability to impart a self-amplified response to a solid stimuli-

responsive material would i) bring about large changes in global properties of the

material in response to a specific signal; ii) substantially increase the rate of change in the

material; and iii) decrease the amount of signal required to induce the transformation.2

Since depolymerization is based on the interaction of a specific analyte with a

reaction-based detection group, the rate with which the CDr polymer-based material

depolymerizes in the solid state is determined largely by the number of responsive

functional groups found at the surface of the plastic material2,3

(Figure 3-1b). As the

number of detection groups at the surface is increased, so too are the opportunities for

initiating depolymerization of a polymer chain with a signal in the air or fluid that

contacts the material. Thus, a polymer containing only a single detection group at the

terminus of the polymer (Figure 3-1a) possesses limited opportunities to interact with the

surrounding substrate, as a significant portion of the reactive groups likely are buried

beneath the surface of the hard plastic. Typically, a small amount (less than 1%) of

detection groups in these polymers are accessible to a stimulus in the surrounding

64

solution.3 Once all available detection groups at the solid-liquid interface have been

exhausted, the solid-state plastic often ceases to depolymerize.

Figure 3-1. a) Depolymerization mechanism of a poly(benzyl ether) containing a single

reaction-based detection group at the terminus of the polymer. b) Cross section of a

plastic depicting accessibility of detection groups at the solid-liquid interface of the

material.2 Adapted with permission from J. Am. Chem. Soc. 2015, 137 (16), 5324−5327.

Copyright 2015 American Chemical Society.

Using fluoride-responsive poly(benzyl ethers) as a model, Yeung and coworkers

previously demonstrated that the number of accessible detection groups can be increased

by attaching detection units to each repeating unit along a polymer chain2 (Figure 3-2).

While this modification increases the likelihood of reaction between an applied signal

and a detection unit, the magnitude of signal amplification achieved from a single

accessible to a stimulus in solution

inaccessible to a stimulus in solution

a)

b)

65

detection event decreases compared to CDr polymers that contain a single detection unit

at the terminus. This decrease in amplification occurs because head-to-tail

depolymerization in poly(benzyl ethers) is unidirectional, thus polymer fragments remain

upstream of the initial reaction location in the polymer backbone.

Figure 3-2. a) Mechanism of depolymerization for a CDr poly(benzyl ether) with

detection groups on each monomer unit. b) Cross section of a hard plastic comprised of

polymers illustrated in Figure 3-2a.2 Reproduced with permission from J. Am. Chem. Soc.

2015, 137 (16), 5324−5327. Copyright 2015 American Chemical Society.

Figure 3-3. Substituted poly(benzyl ethers) containing one fluoride detection group at the

terminus of the polymer (3-1), fluoride detection groups on every repeating unit (3-2),

and a control polymer containing no fluoride-responsive detection groups (3-3).

a) b)

66

Yeung and coworkers illustrated the stark difference of reaction rate between a

poly(benzyl ether) containing a single detection group (3-1), and a poly(benzyl ether)

with pendant detection groups on each repeating unit of the polymer2 (3-2) (Figure 3-3).

Discs fabricated from each polymer were submersed in a 3.6 M solution of tetra-n-

butylammonium fluoride (TBAF) in MeCN. While polymer 3-1 initially exhibits

diffusion of the colored monomer species, the available detection groups are quickly

consumed and the remaining polymer disc is stable for one week (Figure 3-4). In

contrast, polymer 3-2 depolymerizes completely under identical conditions over the

course of four hours (Figure 3-5). Control polymer 3-3, containing no silyl ether

detection groups, shows no depolymerization over the course of a week (Figure 3-6).

Figure 3-4. Photographs of solid-state studies with a disc prepared from polymer 3-1 (Mn

= 6.8 kDa) after exposure to 3.6 M TBAF in MeCN. After the fluoride solution is added,

a purple/yellow color is generated, indicating depolymerization is occurring, yet the disc

remains intact over the course of a week.2 Reproduced with permission from J. Am.

Chem. Soc. 2015, 137 (16), 5324−5327. Copyright 2015, American Chemical Society.

67


= 5.0 kDa) after exposure to 3.6 M TBAF in MeCN. After the fluoride solution is added,

a deep purple color is generated, indicating that depolymerization is occurring. Complete

depolymerization transpires in 4.5 h.2 Reproduced with permission from J. Am. Chem.

Soc. 2015, 137 (16), 5324−5327. Copyright 2015, American Chemical Society.


= 4.6 kDa) exposed to 3.6 M TBAF in MeCN. The polymer disc remains completely

intact over the course of one week.2 Reproduced with permission from J. Am. Chem. Soc.

2015, 137 (16), 5324−5327. Copyright 2015, American Chemical Society.

68


Not only is solid state depolymerization required for certain applications of

stimuli-responsive materials, but so too is the ability of these materials to respond to

specific analytes in aqueous environments. We hypothesized that both of these

characteristics could be addressed by increasing the hydrophilicity of the detection

groups on each unit of the polymer chain. By creating a localized area of higher polarity

near the detection unit, this portion of the polymer will preferentially orient at the solid—

water interface in place of the more hydrophobic polymer backbone.

DiLauro and coworkers previously studied the effect that varying polarity of

polymer end cap detection units has on rates of depolymerization in the context of

fluoride-responsive poly(phthalaldehyde) films.3 They found that detection groups

became more accessible to surrounding stimuli in an aqueous solution when the polarity

was increased on silyl ether detection groups at the terminus of the polymer (Figure 3-7).

Figure 3-7. Poly(phthalaldehyde) end-capped with silyl ethers of differing polarity.

DiLauro and coworkers showed polar end-cap detection units increase the rate of

depolymerization in responsive polymer films.3 Adapted with permission from

Macromolecules 2013, 46 (18), 7257−7265. Copyright 2013 American Chemical Society.

increasing polarity

increases end-

cap accessibility

69

We have now tested a similar hypothesis using solid-state depolymerization of

poly(benzyl ethers) by synthesizing a series of palladium-responsive polymers containing

allyl ether groups of varying polarity on each repeating unit (Figure 3-8). This trio of

polymers includes standard allyl ether polymer 3-4 (medium polarity), n-dodecenyl-

substituted polymer 3-5 (low polarity), and PEG-substituted polymer 3-6 (high polarity).

While we expected to see an increase in depolymerization rate with the hydrophilic

polymer, we also synthesized a hydrophobic polymer to determine if the hypothesis could

also be applied in the opposite direction. Our primary reason for initiating this study was

to determine whether the favorable polarity effects observed by DiLauro will be relevant

in a polymer with detection groups on each repeating unit.

Figure 3-8. A series of poly(benzyl ethers) containing various degrees of polarity on the

allyl ether reaction-based detection unit.

Qualitative time lapsed photographs of discs of polymers 3-4, 3-5, and 3-6

provided visual evidence for the rate of depolymerization in response to palladium (0).

Surface characteristics of each polymer film also were studied using a contact angle

goniometer, scanning electron microscopy (SEM), and atomic force microscopy (AFM)

to correlate reaction rates with surface polarity and microscopic structure.

70


3.3.1 Synthesis of the Monomers

Quinone methide monomers containing pendant detection groups of varying

polarity (3-7, 3-8, 3-9) were prepared using short syntheses (3 steps, 28–39% yields), and

were polymerized under anionic conditions to produce polymers 3-4, 3-5, and 3-6

(Figures 3-9, 3-10, and 3-11), respectively.

Figure 3-9. Synthetic scheme for monomer 3-7.


71


3.3.2 Synthesis of Poly(benzyl ethers)

Phosphazene base (P1-t-Bu) and methanol were used to initiate polymerization.

The reaction temperature is held at −20 oC for one hour, and then the polymer is end-

capped with acetic anhydride and slowly warmed to room temperature (Figure 3-12).

Figure 3-12. Conditions for anionic polymerization of poly(benzyl ethers) 3-4, 3-5, and

3-6 as well as corresponding data for each polymer used in depolymerization studies.

(Mn = molecular weight, DP = degree of polymerization, PDI = polydispersity index).

R Mn (kDa) DP PDI Yield (%)

3-4 77.0 ± 2.0% 262 1.4 82

3-5 30.6 ± 0.9% 71 1.5 61

3-18 39.3 ± 2.0% 114 1.2 84

72

Polymerization yields generally exceeded 80% with the exception of polymer 3-5,

which suffered due to poor solubility of the monomer under optimized polymerization

conditions. The synthesis of 3-6 requires a post-polymerization azide-alkyne

cycloaddition, which allows for efficient coupling of hydrophilic, reactive, or unstable

functional groups to the polymer without sacrificing yield or length during

polymerization (Figure 3-13). Due to the hygroscopic nature of PEG-functionalized

monomers, it proved difficult to obtain consistent, controllable length and dispersity

values for polymer 3-6 without the use of post-polymerization modification.

Figure 3-13. The azide/alkyne cycloaddition used to complete the synthesis of 3-6.

3.3.3 Solution Phase Studies for Selective Depolymerization of Poly(benzyl ethers)

We first evaluated how each poly(benzyl ether) responds when exposed to

palladium (0) in solution, using gel permeation chromatography (GPC) to monitor the

depolymerization reaction (Figure 3-14). For example, treatment of polymer 3-4 (Mn =

72.8 kDa, 17 mM) with Pd(PPh3)4 (34 mM) and 1-8-diazabicycloundec-7-ene DBU (85

mM) in THF showed complete depolymerization after 1 h (Figure 3-15a). The reaction

73

mixture quickly turned a deep purple color, indicating release of deprotected monomer 3-

19. Polymer 3-6 (70.1 kDa, 8.6 mM) also depolymerized completely when exposed to

Pd(PPh3)4 (17 mM) and DBU (85 mM) in THF, but at a slower rate than polymer 3-4

(Figure 3-15b). This decreased rate might occur as a result of the steric bulk neighboring

the functional allyl ether in polymer 3-6. Very little or no depolymerization was observed

for both polymers in the absence of Pd(PPh3)4 (Figure 3-16).

Figure 3-14. Depolymerization reaction and conditions used for solution phase studies.

Figure 3-15. Responses of polymers a) 3-4 and b) 3-6 as monitored by GPC after

exposure to Pd(PPh3)4 (34 mM) and DBU (85 mM) in THF.

Elapsed time (h):0.0, 1.0, 3.0

Elapsed time (h):0.0, 0.5, 1.0

GP

C R

efr

acti

ve I

nd

ex

GP

C R

efr

acti

ve I

nd

ex

Retention Time (min) Retention Time (min)

a) b)

74

Figure 3-16. Control studies of polymers a) 3-4 and b) 3-6 as monitored by GPC in the

presence of DBU (85 mM) in THF and 0 mM Pd(PPh3)4.

3.3.4 Solid-State Depolymerization of Poly(benzyl ethers)

We subsequently evaluated the response of each poly(benzyl ether) when exposed

to palladium (0) in the solid state. To fabricate polymer materials for solid-state

depolymerization studies, each polymer was drop-cast into a silicon mold and dried under

high vacuum. More specifically, a solution of polymer in toluene (100 mg/mL) and 20%

wt. plasticizer (dibutyl phthalate) was deposited into the mold at regular intervals,

following evaporation of the previously deposited solution. The disc was air-dried and

then placed in a high vacuum chamber for 24 h.

Each disc made from polymers 3-4, 3-5, and 3-6 was suspended in a solution of

100 μL DBU in 19 mL H2O, then 20 mg Pd(PPh3)4 was added to the vial as a solution in

THF (1 mL) (Figure 3-17). Polymer 3-4 showed little indication of depolymerization

over the first 10 h of exposure to palladium. By 25 h, the polymer began to turn a

purple/red color, which is indicative of depolymerization (Figure 3-17a). The material

Elapsed time (h):0.0, 24.0

Elapsed time (h):0.0, 24.0

GP

C R

efr

acti

ve I

nd

ex

GP

C R

efr

acti

ve I

nd

ex

Retention Time (min) Retention Time (min)

a) b)

75

slowly released monomers into the surrounding solution, yet the disc maintained a

constant shape over 100 h of reaction time.

In contrast, polymer 3-6 began changing color and releasing monomers much

faster than 3-4 (Figure 3-17b). By approximately 30 h the polymer had depolymerized

completely, leaving only a residue at the bottom of the vial, which we observe frequently

when the palladium catalyst becomes inactive. Finally, polymer 3-5 displayed a similar

response to polymer 3-4, as a significant portion of the polymer disc still remained after

100 h of exposure to the analyte in solution (Figure 3-17c).

Figure 3-17. Time lapsed photographs of the solid-state depolymerization of discs

prepared from polymers a) 3-4, b) 3-6, and c) 3-5. Each polymer was submerged in 20

mL of a 95% H2O−THF solution containing 20 mg Pd(PPh3)4 and 100 μL DBU.

Time (h) 0 5 15 25 33

Time (h) 0 5 25 50 100

Time (h) 0 5 25 50 100

3-4

3-6

3-5

a)

b)

c)

76

Control tests also were performed in the absence of palladium (0). Each polymer

disc was photographed for one week while suspended in a 95% H2O−THF solution

containing 100 μL DBU (Figure 3-18a). No change was observed in the shape of polymer

3-4 over the course of one week, while polymer 3-6 exhibited swelling and slight color

changes during the same time period (Figure 3-18b). This change in color and size is

likely due to a small number of hydrolysis events occurring at the acetate end-cap of the

polymer that makes up the disc. The basic reaction mixture has greater access to the end-

caps of polymer 3-6 as opposed to polymer 3-4 due to swelling properties and the

increased hydrophilic nature of the material.

Figure 3-18. Photographs of solid-state control studies with discs prepared from

polymers a) 3-4 and b) 3-6 in the absence of palladium. Each polymer disc was

photographed for one week while suspended in a 19:1 H2O−THF solution containing 100

μL DBU.

Time (d) 0 1 3 5

3-4

3-6

a)

b)

77

GPC analysis of the surrounding solution following solid-state control tests of

polymers 3-4 and 3-6 confirmed that the polymer disc was not dissolving or diffusing

into the surrounding aqueous solution. After two months, aliquots of the solution were

removed and injected into the GPC (Figure 3-19).

Figure 3-19. Gel permeation chromatograms of a) 3-4 and b) 3-6 comparing the initial

polymer from which the disc is made (black), and the solution surrounding the disc

following two months of submersion in THF, H2O, and DBU (blue).

3.3.5 Verification of the Head-to-Tail Depolymerization Mechanism

To confirm that polymer 3-6 is depolymerizing from head-to-tail, we performed a

series of analytical tests on the solution surrounding the solid-state disc in Figure 3-17b.

The absence of polymer 3-6 from the surrounding solution was verified by GPC (Figure

3-20). Additionally, LCMS analysis of the surrounding solution identified deprotected

quinone methide 3-19 (M + H+ = 255.1) as well as unreacted PEG monomer 3-20 (M +

H+ = 580.2) (Figure 3-21). The presence of both products confirms that the polymer

depolymerizes through a head-to-tail mechanism without requiring allyl ether

deprotection on each unit in order for depolymerization to occur.

5 15 25 5 15 25G

PC

Re

frac

tive

In

de

x

Retention Time (min)

GP

C R

efr

acti

ve I

nd

ex


a) b)

78

Figure 3-20. GPC analysis of the surrounding solution (blue) from solid-state

depolymerization tests of polymer 3-6 (black), indicating only small molecules remain.

Figure 3-21. LCMS analysis of the solution surrounding the solid-state studies of 3-6

after being exposed to Pd(PPh3)4 and DBU in THF. Masses of both deprotected monomer

3-19 and unreacted monomer 3-20 indicate successful head-to-tail depolymerization.

GP

C R

efr

acti

ve In

de

x


3-19M+ H+ = 255.1

3-20M + H+ = 580.2

O=PPh3

DBU

79

3.3.6 Characterization of Material properties

In addition to reaction-based studies, we analyzed the material properties of the

discs made from polymers 3-4, 3-5, and 3-6. Contact angle measurements of each

polymer were obtained using goniometry. Films were created by spin-casting 10 mg/mL

solutions of each polymer in chloroform onto glass slides, which were then dried in a

vacuum oven overnight. High-resolution photographs were taken of 5 μL water droplets

on the polymer films. The contact angles from polymer 3-6 were found to e

approximately 25 less than those from hydrophobic polymers 3-4, and 3-5 (Figure 3-22).

The measurements shown are an average of three trials. The enhanced hydrophilicity of

polymer 3-6 indicates that the wettability of the polymeric material allows it to interact

more favorably with the surrounding solution, and this characteristic likely plays an

important role in determining the rate of depolymerization in the solid state.

Figure 3-22. Contact angle measurements of polymer films fabricated by spin-casting of

polymers 3-4, 3-5, and 3-6 on glass substrates.

The surface morphologies of the polymer discs were characterized using FE-SEM

imaging (Figure 3-23). At 5,000× magnification, the surfaces of 3-4 and 3-6 appear to be

96.3 ± 1.04°93.9 ± 1.25° 69.7 ± 0.25°

3-4 3-5 3-6

80

smooth and relatively free of imperfections or changes in surface area. These images

provide little indication that surface characteristics of PEG-substituted polymer 3-6 are a

significant factor in its increased rate of solid-state depolymerization. Additionally, the

lack of significant roughness on polymers 3-4 and 3-6 indicates that there are no

morphological changes which affect the contact angle measurements in Figure 3-23.

Thus, the difference in contact angle likely is caused primarily by the pendant chemical

functionalities on the polymer backbone.

Figure 3-23. SEM images showing the surface morphologies of polymer discs fabricated

from 3-4, 3-5, and 3-6 at 5,000× magnification.

10 μm

3-4 3-5

3-6

10 μm 10 μm

81

Films comprised of polymers 3-4, 3-5, and 3-6 (with 20 wt% plasticizer) were

spin-coated onto mica discs and used to acquire Young’s modulus values (the resistance

of a substance to elastic deformation) via Atomic Force Microscopy (AFM) (Figure 3-

24). Measurements exhibited a significant dichotomy in rigidity between polymer 3-4

(1303 ± 96.2 MPa) and polymers 3-5 (29.5 ± 3.3 MPa) and 3-6 (32.7 ± 1.7 MPa).

Previous methods used to increase detection group accessibility in solid-state materials

have not compromised or changed the overall rigidity of the plastic.2,3

In this case

polymer 3-6 is significantly softer than polymer 3-4, but the lack of material rigidity does

not directly lead to rapid solid-state depolymerization. The similar softness of polymer 3-

5 compared to polymer 3-6 indicates that the elastic nature of these polymers is likely not

a primary factor in the increased rate of depolymerization of 3-6.

Figure 3-24. Young’s modulus measurements of 3-4, 3-5, and 3-6 acquired by Atomic

Force Microscopy (AFM). The data are an average of three measurements.

You

ng

’s M

od

ulu

s (M

Pa)

3-4 3-5 3-6

82

3.4 Conclusions

In an effort to induce efficient solid-state depolymerization in predominately

aqueous environments, we have developed a poly(benzyl ether) functionalized with

hydrophilic detection groups on each repeating unit of the polymer chain. This polymer

showed fast rates of depolymerization and increased hydrophilicity compared to

poly(benzyl ethers) with pendant detection groups containing less polar functionalities.

Material property analysis of the polymers indicated that the increased hydrophilicity is a

primary factor in accelerating the rate of solid-state depolymerization in water. We

envision that these results will contribute to the future design of CDr polymers with

applications in mind such as responsive coatings and plastics that are recycled easily and

selectively.

83

3.5 References

(1) Baker, M. S.; Kim, H.; Olah, M. G.; Lewis, G. G.; Phillips, S. T. Depolymerizable

Poly(benzyl Ether)-Based Materials for Selective Room Temperature Recycling.

Green Chem. 2015, 17 (9), 4541–4545.

(2) Yeung, K.; Kim, H.; Mohapatra, H.; Phillips, S. T. Surface-Accessible Detection

Units in Self-Immolative Polymers Enable Translation of Selective Molecular

Detection Events into Amplified Responses in Macroscopic, Solid-State Plastics.

J. Am. Chem. Soc. 2015, 137 (16), 5324–5327.

(3) Dilauro, A. M.; Zhang, H.; Baker, M. S.; Wong, F.; Sen, A.; Phillips, S. T.

Accessibility of Responsive End-Caps in Films Composed of Stimuli-Responsive,

Depolymerizable Poly(phthalaldehydes). Macromolecules 2013, 46 (18), 7257–

7265.

84

Chapter 4

Mechanically-Induced Responses of CDr Polymers

4.1 Introduction to Mechanoresponsive Materials

The pursuit of new stimuli-responsive materials has recently expanded beyond the

scope of chemically- or thermally-induced transformations. Due to the abundant

mechanical energy stored along linear polymer chains, mechanoresponsive materials

have become an attractive approach for inciting chemical transformations with an

externally applied physical stimulus.1,2

Materials capable of remodeling their structural

and physical properties in response to force-induced chain scission could be attractive for

several applications, including medical devices, packaging, and electronics.

The study of mechanical stress on materials was pioneered by Staudinger and

coworkers in the 1930’s.3–5

Early work in the field was predominantly centered on

mechanical degradation, including the measurement of stress loads required to reach

mechanical failure and the resulting effect on polymer chain length. However, a new

focus in this area has been the development of mechanoresponsive materials with

“productive” rather than “destructive” outcomes.1 Instead of leading to mechanical

failure, next generation stimuli-responsive materials are being designed to serve specific

functions upon cleavage of scissile chemical bonds.

Interest in this field expanded with the development of “mechanophores,” a

mechanically-sensitive functionality that undergoes chemical change at specific sites

85

along a polymer chain when exposed to mechanical force. This approach was first

demonstrated by Moore in 2005 with an azo-functionalized poly(ethylene glycol).6

Figure 4-1. A list of mechanophores embedded within polymer chains that are designed

to cleave/activate in the presence of ultrasound sonication. Blue arrows indicate polymer

chains and the direction of applied elongational force.2

86

In the past 10 years, a considerable number of mechanophores have been reported

towards the development of “productive” mechanically-responsive polymers7 (Figure 4-

1). These mechanophores can lead to desired material transformations in response to

mechanical stress, including color/fluorescence changes,8 activation of catalysts,

9–11

isomerizations,12

ring-opening reactions,13,14

and depolymerization.15–17

Structural

changes within mechanoresponsive materials range from simple conformational changes

and chain entanglement to bond-stretching deformations and complete chain scission.

The most commonly used method for applying stress in mechanoresponsive

studies is ultrasound sonication. Pressure variations created by a sonication probe

immersed in a polymer solution will create bubbles, which subsequently collapse and

generate solvodynamic shear. Polymers within the pressure gradient generated by the

cavitation of bubbles elongate in one direction (toward the collapsing bubble), which

induces tension—and ultimately scission—along the polymer backbone (Figure 4-2).1

Figure 4-2. Ultrasound sonication of polymers. Collapsing bubbles create a pressure

gradient, which elongates the polymer, and the resulting tensile forces cleave the polymer

at a weak bond near the center of the chain.1 Reproduced with permission from Chem.

Rev., 2009, 109 (11), 5755−5798. Copyright 2009 American Chemical Society.

87

The rate of chain scission is highly dependent on the degree of polymerization in

mechanoresponsive polymers, as elongational forces acting upon the polymer chain will

increase with polymer length.18

Following an initial scission event, polymer chains will

continue to cleave in the presence of mechanical stress until the length of the polymer

decreases to a point that tensile forces along the polymer backbone are not strong enough

to induce bond cleavage.

The vast majority of scissile bonds studied in the context of mechanoresponsive

materials will cleave homolytically,1,19–21

a postulate that especially holds true for the

rupture of C−C onds. The first instrumental experiments confirming radical formation

were demonstrated by Sakaguchi and Sohma in 1975 through the use of electron spin

resonance (ESR).22–24

Ultimately, radicals forming as a result of bond cleavage may

recombine with the same or another polymer chain, disproportionate, or react with

atmospheric oxygen. While newly formed polymer termini are reactive, small molecule

species are not released from the structure in the form of depolymerization following

homolytic cleavage.

In contrast, a limited number of mechanoresponsive materials will result in

heterolytic cleavage. The possibility of heterolytic scission was initially evidenced by

Aktah and Frank, who used first-principles molecular dynamics calculations to theorize

the heterolytic ond cleavage of C−O onds in a PEG polymer dissolved in water.25

While heterolytic scission was proposed in response to mechanical stress, it required

assistance from nearby water molecules, which immediately trapped the termini

following chain cleavage (Figure 4-3).

88

Figure 4-3. Two proposed mechanisms for the heterolytic cleavage of poly(ethylene

glycol) in water.25

One of the first instances of sonication-induced heterolytic cleavage of a polymer

was reported by Moore and coworkers in 2014 with the use of a triarylsulfonium salt

(TAS) mechanophore.26

Trapping experiments of the newly formed polymer termini with

a secondary amine indicated heterolytic release of a phenyl cation from the

mechanophore following the introduction of mechanical stress (Figure 4-4). This result

was validated with the use of GPC and NMR.

Figure 4-4. The proposed mechanism of the TAS mechanophore cleavage induced by

mechanical stress, and subsequent trapping of the produced cation with a secondary

amine.26

i)

ii)

89

Perhaps the largest step toward creating heterolytically cleavable stimuli-

responsive polymers was achieved recently by Boydston, Moore and coworkers, who

demonstrated the mechanoresponsive qualities of poly(phthalaldehyde).15,16

In the

presence of ultrasound sonication, poly(phthalaldehyde) depolymerizes to monomers

following heterolytic cleavage along the polymer’s acetal-based backbone. A proposed

mechanism suggests the formation of an oxocarbenium cation and hemiacetalate anion,

both of which are capable of facilitating depolymerization in the subsequently formed

polymer fragments (Figure 4-5).

Figure 4-5. The proposed mechanism for heterolytic cleavage and subsequent

depolymerization of poly(phthalaldehyde) in response to applied ultrasound sonication.15

Adapted with permission from Nature Chem. 2014, 6 (7), 623−628. Copyright 2014,

Nature Publishing Group.

The heterolytic mechanism was proposed following a series of trapping

experiments using electrophilic (TBS-Cl and pyridine) and nucleophilic (2-methylindole)

reagents. Poly(phthalaldehyde) solutions were sonicated in the presence of each trapping

reagent (250 equiv), and exhibited a significant reduction of refractive index (RI) signal

compared to a control experiment in the absence of trapping reagents (Figure 4-6).

90

Figure 4-6. A plot of refractive index peak area vs. sonication time of

poly(phthalaldehyde) solutions containing TBS-Cl/pyridine (red), 2-methylindole

(green), and no trapping reagents (blue). Reproduced with permission from Nature

Chem. 2014, 6 (7), 623−628. Copyright 2014, Nature Publishing Group.

4.2 Mechanochemical Responses of CDr Polymers

Confirmation of heterolytic cleavage in poly(phthalaldehyde) provides a

foundation for developing stimuli-responsive materials that depolymerize in the presence

of mechanical force. Theoretically, heterolytic cleavage of CDr polymers should cause

them to depolymerize from head-to-tail, beginning at the point of chain scission. The

development of polymer backbones capable of depolymerizing via heterolytic cleavage

could lead to new applications for materials which exhibit autonomous amplification and

significant degradation in response to mechanical stress. In order to further study the

potential for CDr polymers to be used in mechanoresponsive materials, we performed

experiments exploring the rate and mechanism of cleavage of a series of CDr polymers.

91


We analyzed the responses of three polymer backbones in the presence of

mechanical stress through a series of experiments using an ultrasonic probe processor.

These experiments were designed to investigate three parameters of each polymer: i) the

mechanism of bond cleavage; ii) the ability to depolymerize following a cleavage event;

and iii) the extent to which degree of polymerization affects the rate of chain scission.

Several different lengths of polymers 4-1, 4-2, and 4-3 were synthesized for use in

sonication experiments. Each polymer was synthesized under anionic conditions using an

alcohol initiator and strong phosphazene base (Figure 4-7).

Figure 4-7. Conditions used to synthesize varying lengths of poly(4,5-

dichlorophthalaldehyde) (4-1), poly(benzyl ether) (4-2), and poly(hexylisocyanate) (4-3)

for sonication experiments. Polymer 4-1 was prepared by Anthony DiLauro, Saptarshi

Chatterjee and Christopher Lyon. Polymer 4-3 was prepared by Kelli Ogawa.

92

Solutions of each polymer in THF (1 mg/mL) were transferred to a Suslick cell

and fastened to the sonication apparatus (Figure 4-8). In each experiment, the sonication

probe operated on intervals of one second on, and nine seconds off. By controlling

sonication on/off cycles and maintaining a constant water/ice bath around the glass cell,

we are able to limit any thermal effects that could potentially arise through heating of the

probe. Each figure representing sonication data within this chapter is a function of

sonication “on” time, as opposed to total elapsed time during the course of the

experiment. At regular intervals during the sonication process, aliquots of the solution

were removed and injected into a GPC to obtain molecular weight, molecular

composition, and intrinsic viscosity data. As a compliment to standard polymer response

tests, reagent trapping experiments and NMR analysis were also used to help elucidate

mechanisms of bond cleavage and rate of depolymerization.

Figure 4-8. A typical sonication experiment setup: the Suslick reaction cell containing a

polymer solution is fastened to the sonication probe and immersed in a cooled water bath.

93


4.4.1 Responses from Each Polymer Backbone

Polymers 4-1, 4-2, and 4-3 were initially studied to determine whether the

backbone depolymerizes in response to mechanically-induced bond cleavage. Aliquots of

the polymer solutions were removed from the sonication apparatus and injected into the

GPC in order to observe changes in composition and molecular weight over the course of

one hour. Of the three polymers tested, only poly(4,5-dichlorophthalaldehyde) 4-1

exhibited a loss of RI signal concurrently with the growth of a new peak in the small

molecule region of the GPC trace (Figure 4-9). This result indicates the possible release

of monomers through mechanically-induced depolymerization. NMR studies were used

to confirm that the small molecule byproduct from sonication of 4-1 is the expected 4,5-

dichlorophthalaldehyde (4-4) (Figure 4-10).

Figure 4-9. Gel permeation chromatograms of 4-1 (45.4 kDa, 224 DP) in response to

ultrasound sonication. The polymer peak (left) gradually loses mass over time in

association with an increase of a peak in the small molecule range (right).

12 14 16 18 20

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x


Elapsed Time (min): 0, 1, 5, 10, 20, 40, 60

94

Figure 4-10. a) Nuclear magnetic resonance (NMR) spectrum of 4-4. b) NMR spectra of

polymer 4-1 over time in response to ultrasound sonication. The two peaks of increasing

intensity throughout the experiment correspond to known spectra of pure 4-4.

a

b

a b

4-4

a)

Time (min)

1

20

60

b)

95

Conversely, no increase in RI signal was observed in the small molecule region

during sonication of polymers 4-2 and 4-3, which instead exhibited an increase of RI

signal in the polymer region (Figure 4-11 and Figure 4-12). The increasing RI signal of

each polymer is likely due to a narrowing of polydispersity over time without loss of

polymer mass to small molecules. This evidence suggests that poly(benzyl ethers) and

poly(isocyanates) are cleaved homolytically in response to ultrasonic sonication,

effectively eliminating the potential for subsequent depolymerization.

Figure 4-11. a) GPC analysis of 4-2 (44.2 kDa, 151 DP) in response to ultrasound

sonication. b) Proposed mechanism of cleavage for poly(benzyl ether) polymers.

12 13 14 15 16

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x


Elapsed Time (min): 0, 1, 5, 10, 20, 40, 60a)

b)

96

Figure 4-12. a) GPC analysis of 4-3 (21.0 kDa, 165 DP) in response to ultrasound

sonication. b) Proposed mechanism of cleavage for poly(hexylisocyanate) polymers.

4.4.2 Mechanistic Studies: Trapping Experiments

In order to verify the proposed mechanism of chain cleavage for polymer

backbones, we conducted a series of trapping experiments. Head-to-tail depolymerization

following zwitterionic cleavage of 4-1 may be prevented with the addition of a

nucleophile or electrophile, which may react with the newly formed oxocarbenium or

hemiacetalate to form stable polymer end groups. Successful trapping reactions will lead

to a reduction in depolymerization and subsequent monomer formation throughout the

Elapsed Time (min): 0, 1, 5, 10, 20, 40, 60

9 11 13 15

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a)

b)

97

sonication experiment. Data from each experiment was compared to a control sonication

experiment of 4-1, which solely consisted of a 1 mg/mL polymer solution in THF (Figure

4-13).

Figure 4-13. Gel permeation chromatograms of polymer 4-1 (59.0 kDa, DP = 290) in

THF in response to applied ultrasound sonication with no added trapping reagents.

Sonication of 4-1 (59.0 kDa, DP = 290) in the presence of nucleophilic trapping

reagent 2-methylindole provides evidence of heterolytic chain cleavage due to the

considerable preservation of polymer RI signal (Figure 4-14). This change in the GPC

data indicates the ability for 2-methylindole to react with the newly formed ionic chain

termini. If the chain had instead cleaved homolytically, we would expect to see little to

no change in the GPC data due to the inability for the trapping reagents to react with the

subsequently produced radicals. The use of electrophilic trapping reagent TBS-Cl

provided less convincing data for end-group trapping. However, a direct comparison to

10 11 12 13 14 15 16

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x


Elapsed Time (min): 0, 1, 5, 10, 20, 40, 60

98

the control experiment in Figure 4-13 reveals a decreased rate of depolymerization

(Figures 4-15, and 4-16).

Figure 4-14. a) Gel permeation chromatograms depicting the trapping of hemiacetalate

end-groups produced via sonication of 4-1 via addition into 2-methylindole (250 equiv)

in THF. b) Proposed mechanism of trapping poly(4,5-dichlorophthalaldehyde) with 2-

methylindole.

11 12 13 14 15 16

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C R

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x



b)

99

Figure 4-15. Gel permeation chromatograms depicting the trapping of oxocarbenium

end-groups produced via sonication of 4-1 via addition into TBSCl (250 equiv) in THF.

Figure 4-16. GPC traces depicting polymer end group trapping efficiency following

sonication of 4-1 for 60 minutes Key: 4-1, t = 0 (black), 2-methylindole (blue), TBS-Cl

(red), no trapping reagents (gray).

10 11 12 13 14 15 16

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x



b)

11 12 13 14 15 16

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100

In addition to confirming the previously proposed chain scission mechanism of

poly(phthalaldehyde), we also performed experiments to confirm the hypothesized

homolytic cleavage mechanism of poly(benzyl ethers). Figure 4-17 exhibits nearly

identical GPC trace data seen in sonication experiments conducted on polymer 4-2 both

with and without 2-methylindole. The similarity between the two experiments likely rules

out a heterolytic chain scission mechanism.

Figure 4-17. Sonication experiments of polymer 4-2 (84.1 kDa, DP = 288) in the

presence of a) no trapping reagents and b) 2-methylindole. (250 equiv).

4.4.3 Effect of Degree of Polymerization on Rate of Cleavage

Based on these results, we proceeded to focus on the mechanoresponsive

properties of poly(4,5-dichlorophthalaldehyde) due to its unique ability to depolymerize

in the presence of ultrasound sonication. We subsequently investigated the effect that

degree of polymerization has on the rate of chain scission and depolymerization of

polymer 4-1. Three different lengths of 4-1 (82 kDa (DP = 404), 59 kDa (DP = 290), and

12 13 14 15 16

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12 13 14 15 16

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b)

101

30 kDa (DP = 148)) were used for sonication experiments (Figure 4-18) and analysis via

GPC and NMR.

Figure 4-18. Gel permeation chromatograms displaying responses of polymer 4-1 (a) DP

= 404, b) DP = 290, c) DP = 148) in the presence of ultrasound sonication.

GPC analysis indicates that the rate of chain cleavage and magnitude of

depolymerization increase with polymer length. The rate of production of 4-4 from

sonication of polymer 4-1 was monitored further by NMR. An internal standard

(dimethyl sulfone) was added to the sonication solution in THF, and aliquots of the

solution were removed, concentrated, and dissolved in CDCl3. Over the course of one

hour, NMR peaks corresponding to 4-4 were integrated relative to the internal standard.

We observed first-order kinetics from the reaction by graphing the natural log of NMR

10 12 14 16

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10 12 14 16

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ive

Ind

ex


11 12 13 14 15 16

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a) b)

c)

Elapsed Time (min): 0, 1, 5, 10, 20, 40, 60

102

peak area over time (Figure 4-19). Slopes calculated from linear regressions of this data

present relative rates of 4-4 production, which increase concomitantly with the degree of

polymerization.

Figure 4-19. Graphs illustrating the production of 4-4 in response to ultrasound

sonication of 4-1. The rate of production of 4-4 increases along with degree of

polymerization (as evidenced by the slope of the linear regression). a) DP = 404, b) DP =

290, c) DP = 148.

4.4.4 Cyclization Hypothesis

In theory, polymer 4-1 will depolymerize to completion following a single stress-

induced cleavage event along the polymer backbone. Under these ideal circumstances,

the GPC trace of each time point during a sonication experiment should fall within the

boundary of the initial polymer distribution (from t = 0). However, the GPC data in

y = 0.0857x - 4.0261

-5

-4

-3

-2

-1

0

0 5 10 15 20

ln(N

MR

Inte

grat

ion)

Sonication Time (min)

y = 0.0532x - 4.1009

-5

-4

-3

-2

-1

0

0 5 10 15 20

ln(N

MR

Inte

grat

ion)


y = 0.0777x - 4.1418

-5

-4

-3

-2

-1

0

0 5 10 15 20

ln(N

MR

Inte

grat

ion

)


a) b)

c)

103

Figure 4-18a exhibit formation of new polymer peaks outside the boundary of the initial

polymer distribution, indicating that depolymerization is prematurely terminated to some

extent. While a reduction of RI signal implies the loss of polymer mass, the shift in

retention time during the sonication of 4-1 implies that some polymer chains are being

quenched rather than depolymerizing to completion following bond cleavage.

Since it appears that this phenomenon is most prominent with long polymers, we

hypothesize that oppositely-charged chain termini may be back-biting following multiple

cleavage events along the polymer chain (Figure 4-20). In this case, longer polymer

chains are more likely to undergo multiple cleavage events, which increase the likelihood

that chain termini of opposite charges may subsequently cyclize.

Figure 4-20. Schematic illustration of our hypothesis regarding termination of

depolymerization due to back-biting cyclization of chain termini with opposite charges.

104

4.5 Conclusion and Future Directions

We anticipate that further GPC analysis of sonicated solutions containing polymer

4-1 will reveal discrepancies compared to linear polymers of similar molecular weight.

Cyclic polymers often exhibit different fundamental properties than their linear

analogues, such as glass transition temperature (Tg), hydrodynamic radius (Rh) and

intrinsic viscosity (η).27

In particular, hydrodynamic radius and intrinsic viscosity (a

measurement of a polymer’s a ility to increase the viscosity of a solvent),28

are typically

lower in cyclic polymers due to their more compact architecture.29

Lower measurements

of intrinsic viscosity and hydrodynamic radii of sonicated solutions containing 4-1

compared to standard, unsonicated 4-1 would provide further evidence for cyclization of

polymers as a result of applied mechanical stress.

105

4.6 References

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Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials.

Chem. Rev. 2009, 109 (11), 5755–5798.

(2) Li, J.; Nagamani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive

to Productive. Acc. Chem. Res. 2015, 48 (8), 2181–2190.

(3) Staudinger, H.; Leupold, E. O. Isoprene and Rubber. XVIII. Studies of the

Viscosity of Balata. Ber. Dtsch. Chem. Ges. B 1930, 63, 730–733.

(4) Staudinger, H.; Bondy, H. F. Isoprene and Rubber XIX. The Molecular Size of

Rubber and Balata. Ber. Dtsch. Chem. Ges. B 1930, 63, 734–736.

(5) Hyo, J. Y.; Mirkin, C. A. PCR-like Cascade Reactions in the Context of an

Allosteric Enzyme Mimic. J. Am. Chem. Soc. 2008, 130 (35), 11590–11591.

(6) Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. Ultrasound-

Induced Site-Specific Cleavage of Azo-Functionalized Poly(ethylene Glycol).

Macromolecules 2005, 38 (22), 8975–8978.

(7) Davis, D. a; Hamilton, A.; Yang, J.; Cremar, L. D.; Van Gough, D.; Potisek, S. L.;

Ong, M. T.; Braun, P. V; Martínez, T. J.; White, S. R.; Moore, J. S.; Sottos, N. R.

Force-Induced Activation of Covalent Bonds in Mechanoresponsive Polymeric

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(8) Chen, Y.; Spiering, J. H.; Karthikeyan, S.; Peters, G. W. M.; Meijer, E. W.;

Sijbesma, R. P. Mechanically Induced Chemiluminescence from Polymers

Incorporating a 1,2-Dioxetane Unit in the Main Chain. Nat. Chem. 2012, 4 (7),

559–562.

(9) Piermattei, A.; Karthikeyan, S.; Sijbesma, R. P. Activating Catalysts with

Mechanical Force. Nat. Chem. 2009, 1 (2), 133–137.

106

(10) Tennyson, A. G.; Wiggins, K. M.; Bielawski, C. W. Mechanical Activation of

Catalysts for C-C Bond Forming and Anionic Polymerization Reactions from a

Single Macromolecular Reagent. J. Am. Chem. Soc. 2010, 132 (46), 16631–16636.

(11) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.; Sottos, N. R.;

White, S. R.; Braun, P. V.; Moore, J. S. Proton-Coupled Mechanochemical

Transduction: A Mechanogenerated Acid. J. Am. Chem. Soc. 2012, 134 (30),

12446–12449.

(12) Lenhardt, J. M.; Ong, M. T.; Choe, R.; Evenhuis, C. R.; Martinez, T. J.; Craig, S.

L. Trapping a Diradical Transition State by Mechanochemical Polymer Extension.

Science 2010, 329, 1057–1060.

(13) Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Baudry, J.; Wilson, S.

R. Biasing Reaction Pathways with Mechanical Force. Nature 2007, 446, 423–427.

(14) Brown, C. L.; Craig, S. L. Molecular Engineering of Mechanophore Activity for

Stress-Responsive Polymeric Materials. Chem. Sci. 2015, 6 (4), 2158–2165.

(15) Diesendruck, C. E.; Peterson, G. I.; Kulik, H. J.; Kaitz, J. a; Mar, B. D.; May, P. a;

White, S. R.; Martínez, T. J.; Boydston, A. J.; Moore, J. S. Mechanically Triggered

Heterolytic Unzipping of a Low-Ceiling-Temperature Polymer. Nat. Chem. 2014,

6 (4), 623–628.

(16) Peterson, G. I.; Boydston, A. J. Kinetic Analysis of Mechanochemical Chain

Scission of Linear Poly(phthalaldehyde). Macromol Rapid Commun 2014, 35 (18),

1611–1614.

(17) Svaneborg, C.; Everaers, R.; Grest, G. S.; Curro, J. G. Connectivity and

Entanglement Stress Contributions in Strained Polymer Networks.

Macromolecules 2008, 41 (13), 4920–4928.

(18) May, P. A.; Munaretto, N. F.; Hamoy, M. B.; Robb, M. J.; Moore, J. S. Is

Molecular Weight or Degree of Polymerization a Better Descriptor of Ultrasound-

107

Induced Mechanochemical Transduction? ACS Macro Lett. 2016, 5 (2), 177–180.

(19) Henglein, V. A. Polymerization of Acrylamide Initiated by Ultrasonic. Makromol.

Chem 1954, 14, 15–39.

(20) Henglein, V. A. The Reaction of 2,2-Diphenyl-1-Picrylhydrazyl with Long-Chain

Free Radicals Produced from Ultrasonic Degradation of Poly(methyl

Methacrylate). Makromol. Chem. 1955, 15, 188–210.

(21) Suslick, K. S.; Price, G. J. Applications of Ultrasound to Materials Chemistry.

Annu. Rev. Mater. Sci. 1999, 29, 295–326.

(22) Sohma, J. Mechanochemistry of Polymers. Prog. Polym. Sci. 1989, 14 (4), 451–

596.

(23) Sakaguchi, M.; Sohma, J. ESR Evidence for Main Chain Scission Produced by

Mechanical Fracture of Polymers at Low Temperature. J. Polym. Sci. 1975, 13 (6),

1233–1245.

(24) Sohma, J.; Sakaguchi, M. ESR Studies on Polymer Radicals Produced by

Mechanical Destruction and Their Reactivity. Adv. Polym. Sci. 1976, 20, 109–158.

(25) Aktah, D.; Frank, I. Breaking Bonds by Mechanical Stress: When Do Electrons

Decide for the Other Side? J. Am. Chem. Soc. 2002, 124 (13), 3402–3406.

(26) Shiraki, T.; Diesendruck, C. E.; Moore, J. S. The Mechanochemical Production of

Phenyl Cations through Heterolytic Bond Scission. Faraday Discuss. 2014, 170

(217), 385–394.

(27) Gagliardi, S.; Arrighi, V.; Ferguson, R.; Dagger, A. C.; Semlyen, J. A.; Higgins, J.

S. On the Difference in Scattering Behavior of Cyclic and Linear Polymers in

Bulk. J. Chem. Phys. 2005, 122 (6), 064904.

108

(28) Lyulin, A. V.; Davies, G. R.; Adolf, D. B. Brownian Dynamics Simulations of

Dendrimers under Shear Flow. Macromolecules 2000, 33 (9), 3294–3304.

(29) Li, G.; Donghui, Z. Cyclic Poly(α-Peptoids) and Their Block Copolymers from N-

Heterocyclic Carbene-Mediated Ring-Opening Polymerizations of N-Substituted

N-Carboxylanhydrides. J. Am. Chem. Soc. 2009, 131 (50), 18072–18074.

109

Chapter 5

Materials, Methods, Experimental Procedures, and Characterization

5.1 Materials.

All reactions were performed in flame-dried glassware under a positive pressure

of argon unless otherwise noted. All reagents used were purchased commercially and

were used as received unless otherwise noted. Air-and moisture-sensitive liquids were

transferred by syringe or stainless steel cannula. Tetrahydrofuran (THF), acetonitrile

(MeCN), diethyl ether (Et2O), toluene (PhMe), dichloromethane (DCM), and N,N-

dimethylformamide (DMF) were purified by the method developed by Pangborn et al.,1

unless noted otherwise. Methanol (MeOH) and was dried over activated 3Å molecular

sieves for 24 h and then distilled from fresh activated 3Å molecular sieves. Pyridine and

N,N-diisopropylethylamine (DIEA) were distilled from ninhydrin, dried over activated

5Å molecular sieves for 24 h, and then redistilled from fresh activated 5Å molecular

sieves. Isopropanol (iPrOH) was distilled from calcium hydride and stored over 3Å

molecular sieves. Deionized water was purified using a Millipore-purification system

(Barnstead EASYpure® II UV/UF). Potassium carbonate was dried at 120 °C at 0.65

Torr for 24 h and stored in a desiccator. Acetyl chloride, ethyl formate, and N-

bromosuccinimide were purified according to published procedures.2 Flash column

chromatography was performed as described by Still et al.,3 employing silica gel (60-Å

pore size, 32–63 µm, standard grade, SiliCycle). Thin layer chromatography was carried

out on SiliCycle silica gel TLC (20 × 20 cm w/h, F-254, 250 µm).

110

5.2 Methods.

Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear

magnetic resonance spectra (13

C NMR) were recorded using a Bruker DRX-400 (400

MHz), Bruker AV-360 (360 MHz), Bruker DPX-300 (300 MHz), or Bruker CDPX-300

(300 MHz). Proton chemical shifts are expressed in parts per mission (ppm, δ scale) and

are referenced to chloroform (CDCl3, 7.26 ppm), methanol (CD3OD, 3.31 ppm), dimethyl

sulfoxide ((CD3)2SO, 2.50 ppm), or acetone ((CD3)2CO, 2.05 ppm). Data are represented

in text form as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q

= quarter, m = multiplet and/or multiple resonances, br s = broad singlet, dd = doublet of

doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet), integration, and

coupling constant (J, in Hertz). Carbon chemical shifts are expressed in parts per million

(ppm, δ scale) and are referenced to chloroform (CDCl3, 77.16 ppm), methanol (CD3OD,

49.0 ppm), or acetone ((CD3)2CO, 29.84 ppm).

UV/Vis spectroscopic data was recorded using a Beckman Coulter DU 800

spectrometer. LC-MS data was obtained using an Agilent Technologies 1200 Series

HPLE with a UV detector and a 6120 Series quadrupole mass spectrometer equipped

with an atmospheric pressure chemical ionization chamber. GPC analyses were

performed using multiple instruments 1) A Viscotek model 270 Dual Detector with right-

and left-angle light scattering, and a Viscotek T-column (300 × 7.8 mm, CLM3012) and

Agilent Resipore column (300 × 7.5 mm) in series using THF as the mobile phase (flow

rate = 1mL/min). The GPC was calibrated using monodisperse polystyrene standards

from Malvern. 2) an Agilent Technologies 1260 GPC equipped with a Wyatt

Technologies Dawn 8+ light scatterer, a Wyatt Technologies ViscoStar-II viscometer, a

111

Wyatt Technologies Optilab T-rEX refractive index detector, and an Agilent PLbel 10

μm MIXED-BLS column using THF as the mobile phase (flow rate = 1 mL/min, 25 °C).

The GPC was calibrated using monodisperse polystyrene standards from Wyatt

Technologies. Scanning electron microscopy (SEM) images were obtained using a Zeiss

Sigma FESEM, and contact angles were measured using a Ramé-Hart automated

goniometer equipped with a digital camera. Contact angles of H2O droplets (5 µL) on

dried polymer films were analyzed using the software DROPimage Advanced.

Photographs were acquired using a Nikon digital camera (D3100).

112

5.3 Chapter 1: Experimental Procedures and Characterization

Figure 5-1. Synthetic scheme for compound 1-25.

(1-19). Sodium hydroxide (NaOH) (6.35 g, 178.4 mmol, 4.0 equiv) was added to

a stirring solution of 9-oxofluorene-4-carboxylic acid (1-18) 10.0 g, 44.6 mmol, 1 equiv)

in diethylene glycol (90 mL, 0.5 M) was added and continued stirring at room

temperature until homogenous. Hydrazine monohydrate (6.5 mL, 133.7 mmol, 3 equiv)

was then added dropwise, and the mixture was heated to 120 °C for 20 minutes (or until

N2 production was visible). The mixture was then stirred for 20 minutes without further

heating, and then reheated to 120 °C for another 2 h. The mixture was again cooled to

room temperature and poured over 200 mL of ice, then acidified to pH 5 with

concentrated HCl (ca. 30 mL). The precipitated solid was filtered out, and the resulting

113

crude orange solid was dissolved in acetone and filtered again. The filtrate was dried over

MgSO4 and concentrated via rotary evaporation. The resulting crude orange mixture was

purified via flash column chromatography (10% ethyl acetate in hexanes) and dried under

high vacuum to afford compound 1-19 as a white solid (6.93 g, 30.9 mmol, 74%). 1H

NMR (400 MHz, ((CD3)2SO): δ 13.24 (s, 1 H), 8.33 (d, 1 H), 7.77 (d, 1 H), 7.73 (d, 1 H),

7.61 (d, 1 H), 7.41 (m, 3 H), 3.97 (s, 2 H); 13

C NMR (400 MHz, (CDCl3): δ 170.0, 1451,

144.5, 140.0, 139.4, 128.5, 128.1, 127.8, 127.0, 126.7, 125.4, 124.7, 36.9. The NMR data

matches the known spectra for this compound.4

(1-20). 2-methyl-2-propene (40 mL, 463.7 mL, 15 equiv) was condensed in a −78

°C dry ice/acetone bath, then transferred via cannula to a stirred solution of compound 1-

19 (6.5 g, 30.9 mmol, 1 equiv) in 10:1 dioxane-H2SO4 (66 mL) at −15 °C for 72 h under

argon. The reaction was slowly warmed to room temperature, and then vented with a

syringe needle through the septum to release excess 2-methyl-2-propene. The reaction

mixture was then poured over 200 mL of cold 1:1 1M NaOH−Et2O. The organic layer

was removed, and the aqueous layer extracted with Et2O (4 × 75 mL). The organic

fractions were combined, dried over MgSO4 and concentrated via rotary evaporation. The

crude residue was then purified by flash column chromatography (0.5% ethyl acetate in

hexanes) and dried under high vacuum to afford compound 1-20 as a white solid (5.34 g,

25.4 mmol, 65%). 1H NMR (400 MHz, (CDCl3): δ 8.36 (d, 1 H), 7.68 (d, 1 H), 7.59 (d, 1

H), 7.49 (d, 1 H), 7.36 (m, 3 H), 3.85 (s, 2 H), 1.87 (s, 9 H). The NMR data matches the

known spectra for this compound.4

(1-21). Sodium hydride (NaH) (1.3 g, 54.1 mmol, 3 equiv) was transferred to a

sealed flask and dried under vacuum for 30 min. NaH was then suspended in Et2O (40

114

mL) and stirred for 5 min. Compound 1-20 (4.80 g, 18.0 mmol, 1 equiv) was added as a

solution in Et2O (30 mL, total reaction concentration: 0.25 M), followed by freshly

distilled ethyl formate (2.90 mL, 36.0 mmol, 2 equiv). The flask was then sealed and

heated to 60 °C for 6 h. The reaction mixture was then cooled to room temperature and

poured over 100 mL ice. The flask was washed with water and added to the ice slurry,

and the resulting aqueous mixture was extracted with a 60:40 mixture of petroleum ether-

Et2O (100 mL). The aqueous layer was then acidified with conc. acetic acid (AcOH) until

it formed a milky white mixture, and was once again extracted with Et2O (3 × 50 mL).

The combined organic layers were washed with brine (2 × 50 mL) then dried over

MgSO4 and concentrated via rotary evaporation for immediate use in the succeeding

reaction.

(1-22). Sodium borohydride (NaBH4) (654 mg, 17.29 mmol, 1 equiv) was added

portion-wise 2 h apart to a stirred suspension of crude compound 1-21 (5.10 g, 17.29

mmol, 1 equiv) in iPrOH (85 mL, 0.2 M). The reaction was stirred for 6 h at room

temperature, then was diluted with H2O (80 mL) and acidified with concentrated AcOH

to pH 5. The mixture was then extracted with Et2O (3 × 50 mL), dried over MgSO4, and

solvent was removed via rotary evaporation. The crude product was then purified by flash

column chromatography (gradient of 10% ethyl acetate in hexanes increasing to 20 %

ethyl acetate in hexanes) and concentrated on high vacuum to afford compound 1-22 as a

pale yellow solid (4.54 g, 15.39 mmol, 85% over two steps). 1H NMR (400 MHz,

(CDCl3): δ 8.90 (d, 1 H), 7.72 (d, 1 H),7.68 (d, 1 H), 7.61 (d, 1 H), 7.41 (m, 3 H), 4.09 (t,

1 H), 4.03 (d, 2 H), 1.68 (s, 9 H); 13

C NMR (400 MHz, (CDCl3): δ 167.9, 146.1, 145.0,

115

140.1, 139.7, 129.1, 128.9, 127.6, 127.4, 126.3, 125.1, 124.7, 124.3, 81.8, 65.2, 49.8,

28.5, 28.3, 28. The NMR data matches the known spectra for this compound.4

(1-23). 1-piperidinecarbonyl chloride (3.15 mL, 25.1 mmol, 4 equiv) was added

via syringe pump over the course of 48 h to a stirring solution of compound 1-22 (1.86 g,

6.28 mmol, 1 equiv) in chloroform (31 mL, 0.25 M) in a flame-dried Schlenk flask. The

flask was heated to 70 °C for the duration of the reaction, which was stirred for an

additional 12 h after all of the reagent was added. The mixture was then cooled to room

temperature and solvent was removed via rotary evaporation. The crude yellow residue

was then purified by flash column chromatography (20% ethyl acetate in hexanes) and

dried via rotary evaporation to isolate 1-23 as a yellow oil (1.70 g, 4.17 mmol, 67%).

Unreacted 1-22 was also collected. 1H NMR (400 MHz, (CDCl3): δ 8.34 (d, 1 H), 7.72 (d,

1 H), 7.70 (d, 1 H), 7.61 (d, 1 H), 7.42 (m, 3 H), 4.42 (m, 2 H), 4.25 (t, 1 H), 3.43 (br, 4

H), 1.69 (s, 9 H), 1.60 (br, 2 H), 1.52 (br, 4 H); 13

C NMR (400 MHz, (CDCl3): δ 171.1,

167.7, 155.2, 145.6, 144.9, 139.8, 139.6, 128.9, 127.6, 126.2, 126.2, 124.8, 124.6, 81.7,

67.1, 60.3, 47.0, 44.9, 28.5, 28.4, 28.2, 25.6, 24.4, 21.0

(1-24). Trifluoroacetic acid (8 mL, 20% v/v) was slowly added to a stirred

solution of compound 1-23 (1.6 g, 3.72 mmol, 1 equiv) in dichloromethane (32 mL, 0.1

M, 80% v/v) at 0 °C. The mixture was stirred for 6 h as the ice bath slowly warmed to

room temperature. The mixture was then washed with brine (2 × 50 mL), dried over

MgSO4 and solvent was removed via rotary evaporation. The resulting residue was

purified by flash column chromatography (20% ethyl acetate in hexanes) and dried via

rotary evaporation to isolate 1-24 as a white solid (1.15 g, 3.27 mmol, 83%). 1H NMR

116

(400 MHz, (CDCl3): δ 8.57 (d, 1 H), 8.03 (d, 1 H), 7.81 (d, 1 H), 7.63 (d, 1 H) 7.42 (m, 3

H), 4.50 (m, 2 H), 4.27 (t, 1 H), 3.4 (br, 4 H), 1.59 (br, 2 H), 1.51 (br, 4 H).

(1-25). BH3−THF (3.0 mL, 31.3 mmol, 20 equiv) was added in two equal portions

12 h apart to a stirred solution of compound 1-24 in THF (8 mL, 0.2 M) at 0 °C. The

reaction was then stirred for an additional 4 h at room temperature. The mixture was then

concentrated and resulting residue was purified via flash column chromatography (20 %

ethyl acetate in hexanes) to afford 1-25 as a white solid (518 mg, 1.53 mmol, 98%). 1H

NMR (360 MHz, (CDCl3): δ 7.96 (d, 1 H), 7.63 (d, 1 H), 7.57 (d, 1 H) 7.43 (t, 1 H), 7.41

(d, 1 H), 7.36 (t, 1 H), 7.31 (t, 1 H), 5.11 (s, 2 H), 4.38 (t, 2 H), 4.26 (t, 1 H), 3.48 (m, 4

H), 1.60 (br, 2 H), 1.53 (br, 4 H).

Figure 5-2. Synthesis of compound 1-15.

(1-15). Phenyl isocyanate (32 μL, 0.30 mmol, 1 equiv) was added to a stirred

solution of compound 1-25 (100 mg, 0.30 mmol, 1 equiv) in toluene (1.5 mL, 0.2 M).

The mixture was stirred at 100 °C for 12 h, the solvent was removed via rotary

evaporation and the resulting crude residue was purified via flash column

chromatography (gradient of 10% ethyl acetate in hexanes increasing to 25% ethyl

117

acetate in hexanes) to afford compound 1-15 (72 mg, 0.16 mmol, 53%) as a white solid.

1H NMR (360 MHz, CDCl3): δ 7.88 (d, 1 H), 7.65 (t, 2 H), 4.74 (m, 8 H), 7.08 (t, 1 H),

6.70 (s, 1 H), 5.61 (s, 2 H), 4.40 (d, 2 H), 4.29 (t, 1 H), 3.47 (m, 4 H), 1.61 (br,2 H), 1.53

(br, 4 H).


(1-16). 4,4’-bismethylenediphenylisocyanate (37 mg, 0.15 mmol, 0.5 equiv) was

added to a flame-dried round-bottom flask and dried under high vacuum, then backfilled

with an argon atmosphere. Compound 1-25 (100 mg, 0.30 mmol, 1 equiv) was added as a

solution in toluene (1.5 mL, 0.2 M) and the reaction mixture was heated at 100 °C for 12

h. The crude mixture was then concentrated via rotary evaporation and purified by flash

column chromatography (gradient of 10% ethyl acetate in hexanes increasing to 25%

ethyl acetate in hexanes) to afford compound 1-16 as a white solid (147 mg, 0.16 mmol,

54%). 1H NMR (400 MHz, (CDCl3): δ 7.86 (d ,2 H), 7.61 (t, 4 H), 7.43 (t, 4 H), 7.33 (m,

8 H), 7.10 (d, 4 H), 6.74 (s, 2 H), 5.59 (s, 4 H), 4.39 (d, 4 H), 4.27 (t, 2 H), 3.87 (s, 2 H),

3.46 (m, 4 H), 1.59 (m, 4 H), 1.54 (m, 8 H).

118


(1-31). 4-Formylbenzoic acid (1-30) (1.56 g, 10.36 mmol, 1 equiv), 2-

hydroxymethyl-1,3-propanediol (330 mg, 3.11, 0.3 equiv), and 4-dimethylaminopyridine

(127 mg, 1.04 mmol, 0.1 equiv) were transferred to a flame-dried flask and dried under

vacuum, then backfilled with an argon atmosphere. The contents were then dissolved in

THF (50 mL, 0.2 M) and cooled to 0 °C. 1 equiv of 1-Ethyl-3-(3-

dimethylaminopropyl)carbodiimide hydrochloride (EDCI∙HCl) (3.0 g, 12.43 mmol, 1.5

equiv) was added and the mixture was slowly warmed to room temperature for 8 h. The

final 0.5 equiv of EDCI∙HCl was then added, and the mixture was stirred at room

temperature for an additional 8 h. The mixture was then concentrated, diluted in ethyl

acetate, and washed with sat. NaHCO3 (2 × 50 mL) and brine (3 × 30 mL), then dried

over MgSO4 and concentrated via rotary evaporation to afford compound 1-30 as a white

solid (1.38 g, 2.75 mmol, 88%). 1H NMR (400 MHz, (CDCl3): δ 10.18 (s, 3 H), 8.20 (d, 6

H), 7.96 (d, 6 H), 4.67 (d, 6 H), 2.95 (m, 1 H).

119

(1-32). To a stirred solution of compound 1-31 (1.00 g, 1.99 mmol, 1 equiv) in 1:2

THF/DCM (30 mL) was added sodium chlorite (3.60 g, 39.8 mmol, 20 equiv) and

monosodium phosphate (5.50 g, 39.8 mmol, 20 equiv), each as a separate solution in H2O

(2 × 10 mL) at room temperature. After stirring for 15 min, 2-methyl-2-butene (4.3 mL,

39.8 mmol, 20 equiv) was added and the reaction stirred for an additional 4 h. The

reaction mixture was then concentrated via rotary evaporation, then diluted in H2O (50

mL) and the solid was filtered out. The solid was then suspended in THF and filtered

once more, then concentrated via rotary evaporation and dried on high vacuum overnight

to afford compound 1-32 as a white solid (804 mg, 1.46 mmol, 73%). The solid was too

insoluble in all solvents to permit NMR analysis.

(1-33). To a suspension of compound 1-32 (400 mg, 0.73 mmol, 1 equiv) in DMF

(7 mL, 0.1 M) was added DIEA (2.50 mL, 14.54 mmol, 20 equiv) and stirred at room

temperature for 3 h. Diphenylphosphoryl azide (DPPA) (1.25 mL, 5.82 mmol, 8 equiv)

was added and the mixture, which was then stirred for 12 h at room temperature. The

mixture was concentrated via rotary evaporation and purified by flash column

chromatography (10% ethyl acetate in hexanes increasing to 20% ethyl acetate in

hexanes) to afford compound 1-33 as a white solid (143 mg, 0.23 mmol, 31%). 1H NMR

(400 MHz, (CDCl3): δ 8.08 (m, 12 H), 4.66 (d, 6 H), 2.93 (m, 1 H).

(1-17). Compound 1-32 (60 mg, .096 mmol, 0.2 equiv) was transferred to a flame-

dried flask and backfilled with an argon atmosphere. Compound 1-25 (162 mg, 0.48

mmol, 1 equiv) was added as a solution in PhMe (1 mL, 0.5M) and stirred at 100 °C for

16 h. The mixture was concentrated and purified via flash chromatography (10% ethyl

acetate in hexanes increasing to 40% ethyl acetate in hexanes) to afford compound 1-17

120

as a white solid (88 mg, .056 mmol, 59%). 1H NMR (360 MHz, (CDCl3): δ 7.94 (d, 6 H),

7.81 (d, 3 H), 7.57 (t, 6 H), 7.44-7.23 (m, 18 H), 5.54 (d, 6 H), 4.54 (d, 6 H), 4.34 (d, 6

H), 4.20 (t, 3 H), 3.43 (br, 12 H), 2.80 (m, 1 H), 1.53 (br, 20 H).

Isolation of Intermediates 1-26, 1-27, 1-29

(1-26, 1-27). A 100 mM stock solution of piperidine (19.8 μL) in THF (2.0 mL,

100 mM) was prepared and 86 μL of this solution (.0086 mmol, 0.1 equiv) was added to

a stirred solution of 1-17 (135 mg, 0.086 mmol, 1 equiv) in THF (770 μL, 110 mM). The

reaction was monitored by TLC, and when an appreciable amount of 1-26 and 1-27 had

formed (~2−3 h), the reaction mixture was concentrated via rotary evaporation. The

intermediates 1-26 and 1-27 were then separated using flash column chromatography

(gradient of 10% ethyl acetate in hexanes increasing to 40% ethyl acetate in hexanes).

Unreacted 1-17 was also collected for use in further isolation reactions.

(1-29). To a stirred solution of 1-16 (196 mg, 0.212 mmol, 1 equiv) in THF (2.1

mL, 100 mM) was added piperidine (2.1 μL, .021 mmol, 0.1 equiv). The reaction was

monitored by TLC, and when an appreciable amount of 1-29 had formed (~5−6 h), the

reaction mixture was concentrated via rotary evaporation. 1-29 was then separated using

flash column chromatography (gradient of 10% ethyl acetate in hexanes increasing to

50% ethyl acetate in hexanes). Unreacted 1-16 was also collected for use in further

isolation reactions.

121

Experimental procedure for studying the reaction mechanisms via LCMS

(1-16). An internal standard stock solution of naphthalene (12.8 mg) in THF (2

mL) was freshly prepared and 146 μL (.0081 mmol, 0.5 equiv) of the solution was added

to 1-16 (15 mg, .0162 mmol, 1 equiv). A stock solution of piperidine (19.8 μL) in THF

(2.0 mL, 100 mM) was freshly prepared, and 16 μL (.00162 mmol, 0.1 equiv) was added

to the solution of 1-16 and naphthalene (for a final concentration of 100 mM 1-16). Every

60 minutes, 2 μL of the solution was removed and diluted in 250 μL THF and injected

into the LCMS. Solution phase: 75% MeCN, 25 % H2O, flow rate: 0.6 mL/min, column:

diphenyl.

(1-17). An internal standard stock solution of naphthalene (12.8 mg) in THF (2

mL) was freshly prepared and 126 μL (.0081 mmol, 0.5 equiv) of the solution was added

to 1-17 (22 mg, .014 mmol, 1 equiv). A stock solution of piperidine (19.8 μL) in THF

(2.0 mL, 100 mM) was freshly prepared, and 14 μL (.0014 mmol, 0.1 equiv) was added

to the solution of 1-17 and naphthalene (for a final concentration of 100 mM 1-17). Every

30 minutes, 2 μL of the solution was removed and diluted in 250 μL THF and injected

into the LCMS. Solution phase: 75% MeCN, 25 % H2O, flow rate: 0.6 mL/min, column:

diphenyl.

**Each peak corresponding reaction product was then integrated against the

internal standard (naphthalene) and graphed as a function of time to demonstrate the

relative amount of each intermediate in the reaction at a given time.

122

Experimental procedure for measuring production of dibenzofulvene via UV/Vis

(1-15). A solution of piperidine (19.8 μL) in THF (2.0 mL) was freshly prepared

and 33 μL (.0033 mmol, 0.1 equiv) were added to a stirred solution of 1-15 (15 mg, .033

mmol, 1 equiv) in THF (295 μL, 110 mM) for a final 1-15 concentration of 100 mM. At

60 min intervals, a 1 μL aliquot was removed and diluted in 1 mL THF. The absorbance

at 310 nm was monitored continuously over time. The reactions were run in triplicate.


and 19.5 μL (.0020 mmol, 0.1 equiv) were added to a stirred solution of 1-16 (18 mg,

.020 mmol, 1 equiv) in THF (176 μL, 110 mM) for a final 1-16 concentration of 100

mM. At 60 min intervals, a 1 μL aliquot was removed and diluted in 1 mL THF. The

absorbance at 310 nm was monitored continuously over time. The reactions were run in

triplicate.


and 14 μL (.0033 mmol, 0.1 equiv) were added to a stirred solution of 1-17 (22 mg, .014

mmol, 1 equiv) in THF (127 μL, 110 mM) for a final 1-17 concentration of 100 mM. At

60 min intervals, a 1 μL aliquot was removed and diluted in 1 mL THF. The absorbance

at 310 nm was monitored continuously over time. The reactions were run in triplicate.

123



(2-19). To a stirred solution of 5-hydroxymethyl-2-furfural (2-18) (1.0 g, 7.93

mmol, 1 equiv) in CHCl3 (40 mL, 0.2 M) at 0 °C was added bromotrimethylsilane (1.57

mL, 11.9 mmol, 1.5 equiv) and slowly warmed to room temperature over 2 h. The

solution was then diluted with DCM (50 mL), washed with H2O (1 × 50 mL) and brine (1

× 50 mL), dried over MgSO4 and the solvent removed via rotary evaporation. The

resulting crude residue was purified using flash column chromatography (gradient of

10% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes) to afford 2-19

as a viscous orange liquid (1.33 g, 7.04 mmol, 89%). 1H NMR (400 MHz, (CDCl3): δ 9.56

(s, 1 H), 7.16 (d, 1 H), 6.56 (d, 1 H), 4.45 (s, 2 H).

(2-20). Potassium carbonate (K2CO3) (1.90 g, 13.76 mmol, 2 equiv) and phenol

(971 mg, 10.32 mmol, 1.5 equiv) were added to a stirred solution of crude compound 2-

21 (1.30 g, 6.88 mmol, 1 equiv) in DMF (34 mL, 0.2 M). The mixture was stirred for 12

124

hours at 50 °C, then cooled to room temperature and concentrated via rotary evaporation.

The crude mixture was then diluted in ethyl acetate (50 mL) and washed with H2O (50

mL). The organic layer was washed with 1 M NaOH (3 × 50 mL) and brine (2 × 50 mL),

dried over MgSO4 and concentrated. The crude material was then purified via flash


ethyl acetate in hexanes) to afford compound 2-20 (1.07 g, 5.29 mmol, 77% over two

steps). 1H NMR (400 MHz, (CDCl3): δ 9.62 (s, 1 H), 7.32 (t, 2 H), 7.22 (d, 1 H), 6.99 (t, 1

H), 6.96 (d, 2 H), 6.61 (d, 2 H), 5.08 (s, 2 H).

(2-21). NaClO2 (3.83 g, 42.33 mmol, 8 equiv) and NaH2PO4∙H2O (5.84 g, 42.33

mmol, 8 equiv) as a solution in H2O (26 mL, 0.2 M) were added to a stirred solution of

compound 2-20 (1.07 g, 5.29 mmol, 1 equiv) in acetone (26 mL, 0.2 M). 2-methyl-2-

butene (4.48 mL, 42.33 mmol, 8 equiv) was added dropwise, and the resulting mixture

was stirred vigorously for 2 h at room temperature. The reaction mixture was then diluted

with ethyl acetate (30 mL) and washed with 1 M HCl (1 × 30 mL), brine (2 × 30 mL),

saturated sodium thiosulfate (1 × 30 mL), and brine (1 × 30 mL). The resulting organic

layer was then dried over MgSO4 and concentrated via rotary evaporation to afford

compound 2-21 as a white solid (1.10 g, 5.04 mmol, 96%). 1H NMR (400 MHz,

(CD3)2CO): δ 11.18 (s, 1 H), 7.32 (t, 2 H), 7.22 (d, 1 H), 7.04 (d, 2 H), 6.96 (s, 1 H), 6.71

(d, 1 H), 5.14 (s, 2 H).

(2-22). Oxalyl chloride (400 μL, 4.77 mmol, 2 equiv) was added dropwise to a

stirred solution of compound 2-21 (520 mg, 2.38 mmol, 1 equiv) in DCM (24 mL, 0.1 M)

and catalytic DMF (100 μL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min

and then warmed to room temperature. The solvent was removed via rotary evaporation

125

and then dried further on high vacuum for 15 min. The crude mixture was then diluted in

acetone (12 mL, 0.2 M) and cooled to 0 °C. Sodium azide (465 mg, 2.42 mmol, 3 equiv)

was added as a solution in H2O (12 mL, 0.2 M), and the resulting mixture was stirred at 0

°C slowly warming to room temperature over 2 h. It was then diluted in ethyl acetate (20

mL), and the organic layer removed. The aqueous layer was extracted with ethyl acetate

(3 × 20 mL), the combined organic fractions were dried over MgSO4 and concentrated

via rotary evaporation. The crude residue was purified via flash column chromatography

(20% ethyl acetate in hexanes) to afford compound 2-22 as a pale tan solid (553 mg, 2.27

mmol, 95%). 1H NMR (400 MHz, (CDCl3): δ 7.32 (t, 2 H), 7.25 (d, 1 H), 7.00 (t, 1 H),

6.96 (d, 2 H), 6.56 (d, 1 H), 5.08 (s, 2 H).

(2-23). Compound 2-22 (100 mg , 0.411 mmol, 1 equiv) and 9-fluorenemethanol

(81 mg, 0.411 mmol, 1 equiv) were dried under vacuum, backfilled with an argon

atmosphere, and then dissolved in toluene (3.0 mL, 0.15 M). The solution was heated for

6 h at 90 °C, cooled to room temperature and the solvent removed via rotary evaporation.

The resulting crude residue was purified via flash column chromatography (gradient of

5% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes) to afford

compound 2-23 as an off-white solid (76 mg, 0.185 mmol, 45%).1H NMR (400 MHz,

(CDCl3): δ 7.82 (d, 2 H), 7.63 (d, 1 H), 7.45 (t, 2 H), 7.31 (m, 5 H), 6.98 (m, 3 H), 6.42

(d, 1 H), 6.11 (br, 1 H), 4.92 (s, 2 H), 4.53 (d, 2 H), 4.30 (t, 1 H).

(2-24). Compound 2-23 (100 mg , 0.411 mmol, 1 equiv) and allyl alcohol (42 μL,

0.617 mmol, 1.5 equiv) were dried under vacuum, backfilled with an argon atmosphere,

and then dissolved in toluene (3.0 mL, 0.15 M). The solution was heated for 6 h at 90 °C,

126

cooled to room temperature and the solvent removed via rotary evaporation. The

resulting crude residue was purified via flash column chromatography (gradient of 5%

ethyl acetate in hexanes increasing to 10% ethyl acetate in hexanes) to afford compound

2-24 as an pale yellow solid (31 mg, 0.114 mmol, 27%).1H NMR (400 MHz, (CDCl3): δ

7.31 (m, 3 H), 6.97 (m, 3 H), 6.40 (d, 1 H), 6.10 (br, 1 H), 5.96 (m, 1 H), 5.33 (dd, 2 H),

4.91 (s, 2 H), 4.68 (d, 2 H).


(2-30). To a stirred solution of 5-hydroxymethyl-furan-2-carboxylic acid (2-29)

(1.0 g, 7.04 mmol, 1 equiv) in DMF (40 mL) at 0 °C was added pyridinium dichromate

(10.53 g, 28.15 mmol, 4 equiv) as a solution in cold DMF (30 mL). The solution was then

stirred at 0 °C for 7 h. The reaction mixture was diluted in Et2O and the solid precipitate

filtered out through Celite. The resulting crude mixture was then concentrated via rotary

evaporation and purified using flash column chromatography (gradient of 50% ethyl


127

as a yellow oil (710 mg, 5.07 mmol, 72%). 1H NMR (300 MHz, (MeOD): δ 9.67 (s, 1 H),

7.38 (d, 1 H), 7.10 (d, 1 H).


stirred solution of compound 2-30 (710 mg, 5.07 mmol, 1 equiv) in DCM (35.0 mL, 0.15

M) and catalytic DMF (50 μL) at 0 °C. The mixture was stirred at 0 °C for 30 min and

then warmed to room temperature. The solvent was removed via rotary evaporation, and

then dried further on high vacuum for 15 min. The crude mixture was then diluted in

acetone (18.0 mL, 0.3 M) and cooled to 0 °C. Sodium azide (990 mg, 15.21 mmol, 3

equiv) was added as a solution in H2O (18.0 mL, 0.3 M), and the resulting mixture was

stirred at 0 °C for 1 h. It was then warmed to room temperature, diluted in ethyl acetate

(30 mL), and the organic layer removed. The aqueous layer was extracted with ethyl

acetate (3 × 30 mL), the combined organic fractions were dried over MgSO4 and

concentrated via rotary evaporation. The crude residue was purified via flash column

chromatography (20% ethyl acetate in hexanes) to afford compound 2-31 as a pale tan

solid (448 mg, 2.71 mmol, 54%). 1H NMR (300 MHz, (CDCl3): δ 9.83 (s, 1 H), 7.34 (d, 1

H), 7.29 (d, 1 H).

(2-32). Compound 2-31 (430 mg, 2.60 mmol, 1 equiv) and phenol (730 mg, 7.80

mmol, 3 equiv) were dried under high vacuum and backfilled with an argon atmosphere,

then dissolved in toluene (26 mL, 0.1 M). The solution was stirred at 90 °C for 10 h,

cooled to room temperature and concentrated via rotary evaporation. The crude residue

was purified using flash column chromatography (50% Et2O in hexanes) to afford

compound 2-32 as a pale yellow oil (380 mg, 1.64 mmol, 63%). 1H NMR (360 MHz,

128

(CDCl3): δ 9.36 (s, 1 H), 9.22 (br, 1 H), 7.44 (t, 2 H), 7.38 (s, 1 H), 7.30 (t, 1 H) 7.22 (d,

2 H), 6.37 (s, 1 H).

(2-33). Sodium borohydride (183 mg, 4.84 mmol, 4 equiv) and acetic acid (830

μL, 14.52 mmol, 12 equiv) were suspended in benzene (20 mL, 0.05 M) and heated to 90

°C for 15 min. Compound 2-32 (280 mg, 1.21 mmol, 1 equiv) was added and stirred at 90

°C for 30 min. The mixture was then cooled to room temperature, diluted in H2O (40

mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were

dried over MgSO4 and concentrated via rotary evaporation. The crude product was

purified via flash column chromatography (gradient of 10% ethyl acetate in hexanes

increasing to 20% ethyl acetate in hexanes) to afford compound 2-33 (40 mg, 0.172

mmol, 14%). 1H NMR (360 MHz, (CDCl3): δ 7.39 (t, 2 H), 7.26 t, 1 H), 7.19, d 2 H), 6.30

(d, 1 H), 6.13 (s, 1 H), 4.55 (s, 2 H).

129


(2-35). NaClO2 (11.47 g, 126.8 mmol, 8 equiv) and NaH2PO4∙H2O (17.50 g,

126.8 mmol, 8 equiv) as a solution in H2O (80 mL, 0.2 M) were added to a stirred

solution of 5-methylthiophene-2-carboxaldehyde (2-34) (2.00 g, 15.85 mmol, 1 equiv)

and 2-methyl-2-butene (13.40 mL, 126.8 mmol, 8 equiv) in acetone (80 mL, 0.2 M). The

resulting mixture was stirred vigorously for 3 h at room temperature. The reaction

mixture was then diluted with ethyl acetate (50 mL) and washed with 1 M HCl (1 × 30

mL), brine (2 × 30 mL), saturated sodium thiosulfate (1 × 30 mL), and brine (1 × 30 mL).

The resulting organic layer was then dried over MgSO4 and concentrated via rotary

evaporation. The resulting solid was purified via flash column chromatography (gradient

of 5% ethyl acetate in hexanes increasing to 40% ethyl acetate in hexanes) to afford

compound 2-35 as a yellow-white solid (2.21 g, 15.54 mmol, 99%). 1H NMR (400 MHz,

(CDCl3): δ 7.71 (d, 1 H), 6.81 (d, 1 H), 2.56 (s, 3 H).

130

(2-36). Benzoyl peroxide (300 mg, 1.24 mmol, 0.2 equiv) was added to a stirred

solution of compound 2-35 (881 mg, 6.20 mmol, 1 equiv) in carbon tetrachloride (30 mL,

0.2 M) and the resulting suspension stirred for 10 min at room temperature. N-

bromosuccinimide (1.65 g, 9.29 mmol, 1.5 equiv) was then added; the mixture was

refluxed for 3 h, and then cooled to room temperature. The reaction mixture was filtered

through Celite and washed with DCM. The solution was concentrated via rotary

evaporation and the resulting residue was purified via flash column chromatography

(gradient of 5% ethyl acetate in hexanes increasing to 40% ethyl acetate in hexanes) to

afford compound 2-37 as a pale yellow solid (877 mg, 3.97 mmol, 64%). 1H NMR (300

MHz, (CD3)2CO): δ 7.02 (d, 1 H), 6.66 (d, 1 H), 4.33 (s, 2 H).

(2-37). Potassium carbonate (K2CO3) (2.33 g, 16.87 mmol, 10 equiv) and phenol

(1.59 g, 16.87 mmol, 10 equiv) were suspended in DMF (8.5 mL, 0.2 M) and stirred at

room temperature for 10 min. Compound 2-36 (373 mg, 1.69 mmol, 1 equiv) was then

added to the suspension as a solution in DMF (8.5 mL, 0.2 M). The mixture was stirred

for 12 hours at 50 °C and then cooled to room temperature. The crude mixture was then

diluted in ethyl acetate (50 mL), washed with sat. NH4Cl (2 × 50 mL) and brine (2 × 50

mL), and then dried over MgSO4 and the solvent was removed via rotary evaporation.

The crude material was then purified via flash column chromatography (gradient of 5%

ethyl acetate in hexanes increasing to 80% ethyl acetate in hexanes) to afford compound

2-37 (224 mg, 0.96 mmol, 57%). 1H NMR (400 MHz, (CDCl3): δ 7.78 (d, 1 H), 7.31 (t, 2

H), 7.11 (t, 1 H), 6.98 (m, 3 H), 5.25 (s, 2 H).


stirred solution of compound 2-37 (161 mg, 0.687 mmol, 1 equiv) in DCM (7 mL, 0.1 M)

131

and catalytic DMF (30 μL) at 0 °C. The mixture was stirred at 0 °C for 30 min and then

warmed to room temperature. The solvent was removed via rotary evaporation, and then

dried further on high vacuum for 15 min. The crude mixture was then diluted in acetone

(3.5 mL, 0.2 M) and cooled to 0 °C. Sodium azide (134 mg, 2.06 mmol, 3 equiv) was

added as a solution in H2O (3.5 mL, 0.2 M), and the resulting mixture was stirred at 0 °C

for 1 h. It was then warmed to room temperature, diluted in ethyl acetate (30 mL), and the

organic layer removed. The aqueous layer was extracted with ethyl acetate (3 × 30 mL),

the combined organic fractions were dried over MgSO4 and concentrated via rotary

evaporation. The crude residue was purified by flash column chromatography (gradient

of 5% ethyl acetate in hexanes) to afford compound 2-39 as a white solid (68 mg, 0.29

mmol, 38%). 1H NMR (400 MHz, (CDCl3): δ 7.75 (d, 1 H), 7.30 (t, 2 H), 7.11 (d, 1 H),

7.01 (t, 1 H), 6.99 (d, 2 H), 5.23 (s, 2 H).

(2-39). Compound 2-38 (40 mg , 0.154 mmol, 1 equiv) and 9-fluorenemethanol

(Fmoc-OH) (30 mg, 0.154 mmol, 1 equiv) were dried under vacuum, backfilled with an

argon atmosphere, and dissolved in toluene (1.5 mL, 0.1 M). The solution was heated for

6 h at 100 °C, cooled to room temperature and the solvent removed via rotary

evaporation. The resulting residue was purified via flash column chromatography

(gradient of 5% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes) to

afford compound 2-39 as a white solid (30 mg, 0.116 mmol, 45%). 1H NMR (400 MHz,

(CDCl3): δ 7.79 (d, 2 H), 7.60 (d, 2 H), 7.41 (t, 2 H), 7.32 (m, 4 H), 7.11 (br, 1 H), 6.98

(m, 3 H), 6.83 (d, 1 H), 6.47 (d, 1 H), 5.11 (s, 2 H), 4.58 (d, 2 H), 4.27 (t, 1 H).

132

(2-40). Compound 2-38 (50 mg , 0.193 mmol, 1 equiv) and was dried under

vacuum, backfilled with an argon atmosphere, and dissolved in toluene (1.5 mL, 0.1 M).

n-butanol (35 μL, 0.579 mmol, 3 equiv) was added, and the solution was heated for 4 h at

100 °C, cooled to room temperature and the solvent removed via rotary evaporation. The

resulting residue was purified via flash column chromatography (gradient of 2% ethyl


as a white solid (39 mg, 0.128 mmol, 66%). 1H NMR (400 MHz, (CDCl3): δ 7.30 (m, 3

H), 6.98 (d, 2 H), 6.82 (d, 2 H), 6.45 (d, 2 H), 5.11 (s, 2 H), 4.19 (t, 2 H), 1.65 (t, 2 H),

1.56 (s, 1 H), 1.39 (t, 2 H), 0.94 (t, 2 H).


(2-35). NaClO2 (43.0 g, 475.5 mmol, 6 equiv) and NaH2PO4∙H2O (65.6 g, 475.5

mmol, 6 equiv) were added as a solution in H2O (300 mL, 0.25 M) to a stirred solution of

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5-methylthiophene-2-carboxaldehyde (2-34) (10.0 g, 79.25 mmol, 1 equiv) in acetone

(200 mL, 0.4 M). 2-methyl-2-butene (50.4 mL, 475.5 mmol, 6 equiv) was added

dropwise, and the resulting mixture was stirred vigorously for 2 h. The reaction mixture

was then diluted with ethyl acetate (150 mL) and washed with 1 M HCl (1 × 75 mL),

brine (2 × 75 mL), saturated sodium thiosulfate (1 × 75 mL), and brine (1 × 75 mL). The

resulting organic layer was then dried over MgSO4 and concentrated via rotary

evaporation to afford compound 2-35 as a white solid (11.0 g, 77.37 mmol, 98%). 1H

NMR (300 MHz, (CDCl3): δ 7.70 (d, 1 H), 6.80 (d, 1 H), 2.55 (s, 3 H).

(2-41). Sulfuric acid (H2SO4) (410 μL, 7.74 mmol, 0.1 equiv) was added to a

stirred solution of compound 2-35 (11.0 g, 77.36 mmol, 1 equiv) in MeOH (230 mL, 0.4

M) and the solution was refluxed for 16 h. The solvent was removed via rotary

evaporation, the resulting residue was dissolved in ethyl acetate (100 mL), washed with

H2O (1 × 50 mL) and brine (2 × 50 mL), dried over MgSO4 and concentrated. The crude

product was purified via flash column chromatography (gradient of 1% ethyl acetate in

hexanes increasing to 2% ethyl acetate in hexanes) to afford compound 2-41 (5.1 g, 32.6

mmol, 42%). 1H NMR (360 MHz, (CDCl3): δ 7.6 (d, 1 H), 6.75 (d, 1 H), 3.83 (s, 3 H),

2.50 (s, 3 H).

(2-42). N-bromosuccinimide (3.36 g, 18.9 mmol, 1.3 equiv) was added to a stirred

solution of compound 2-41 (2.27 g, 14.5 mmol, 1 equiv) in carbon tetrachloride (73 mL,

0.2 M) and the resulting suspension stirred for 10 min at room temperature. Benzoyl

peroxide (704 mg, 2.91 mmol, 0.2 equiv) was then added, the mixture was refluxed for

18 h, and then cooled to room temperature. The reaction mixture was filtered through

Celite, and washed with DCM. The solution was concentrated via rotary evaporation and

134

the resulting residue was purified via flash column chromatography (10% ethyl acetate in

hexanes) to afford compound 2-42 as a pale yellow oil (3.06 g, 13.0 mmol, 90%). 1H

NMR (300 MHz, (CDCl3): δ 7.63 (d, 1 H), 7.09 (d, 1 H), 4.66 (s, 2 H), 3.87 (s, 3 H).

(2-43). Silver (I) p-toluenesulfonate (10.3 g, 37.0 mmol, 1.1 equiv) was added to a

stirred solution of compound 2-42 (7.9 g, 33.6 mmol, 1 equiv) in MeCN (168 mL, 0.2 M)

at 0 °C. The resulting mixture was slowly warmed to room temperature and stirred for 4

h. The mixture was then poured over H2O (200 mL) and extracted with ethyl acetate (3 ×

100 mL), dried over MgSO4 and concentrated via rotary evaporation. The crude residue

was then dissolved in DMSO (70 mL, 0.5 M), NaHCO3 (14.1 g, 168.0 mmol, 5 equiv)

was added, and the suspension was stirred at 100 °C for 1 h. The reaction mixture was

then cooled to room temperature, concentrated via rotary evaporation and purified via

flash column chromatography (gradient of 10% ethyl acetate in hexanes increasing to

20% ethyl acetate in hexanes) to afford 2-43 as a pale yellow oil (2.24 g 13.1 mmol,

39%). 1H NMR (360 MHz, (CDCl3): δ 9.97 (s, 1 H), 7.84 (d, 1 H), 7.75 (d, 1 H), 3.94 (s,

3 H).

(2-44). A 1 M solution of LiOH in H2O (39 mL, 3 equiv) was added to a stirring

solution of compound 2-43 (2.24 g, 13.1 mmol, 1 equiv) in 8:1 THF−MeOH (90 mL,

0.15 M) at 0 °C. The solution was stirred at 0 °C for 4 h then warmed to room

temperature. The solvent was removed via rotary evaporation, diluted in ethyl acetate (75

mL), washed with 1 M HCl (2 × 30 mL) and brine (1 × 30 mL), dried over MgSO4 and

concentrated via rotary evaporation. The crude mixture was purified via flash column


135

acetate in hexanes) to afford compound 2-44 as an off-white solid (1.87 g, 12.0 mmol,

92%). 1H NMR (300 MHz, (CDCl3): δ 10.14 (s, 1 H), 8.14 (d, 1 H), 7.95 (d, 1 H).

(2-45). DPPA (830 μL, 3.84 mmol, 1.2 equiv) was added to a stirring solution of

compound 2-44 (500 mg, 3.20 mmol, 1 equiv) and (DIEA) (830 μL, 4.80 mmol, 1.5

equiv). The solution was heated to 50 °C for 3 h and allowed to cool to room temperature.

The solvent was removed by rotary evaporation and the residue was purified via flash


ethyl acetate in hexanes) to afford compound 2-45 as a white solid (450 mg, 2.47 mmol,

77%). 1H NMR (300 MHz, (CDCl3): δ 9.98 (s, 1 H), 7.88 (d, 1 H), 7.75 (d, 1 H).

(2-46). Compound 2-45 (600 mg, 3.29 mmol, 1 equiv) was dissolved in toluene

(16 mL, 0.2 M) and heated to 100 °C for 30 min. Phenol (1.24 g, 13.2 mmol, 4 equiv)

was added as a solution in toluene (2 mL), and the resulting mixture was heated to 100 °C

for 4 h. The mixture was then cooled to room temperature, the solvent was removed via

rotary evaporation and the resulting residue was purified by flash column


acetate in hexanes) to afford compound 2-46 as an oil (497 mg, 2.01 mmol, 61%). 1H

NMR (300 MHz, (CDCl3): δ 9.80 (s, 1 H), 7.79 (br, 1 H), 7.59 (d, a H), 7.42 (t, 2 H), 7.29

(t, 1 H), 7.22 (d, 2 H), 6.79 (d, 1 H).

(2-47). Sodium borohydride (NaBH4) (80 mg, 2.10 mmol, 4 equiv) was dried

under high vacuum in a flame-dried flask, then backfilled with an argon atmosphere.

NaBH4 was suspended in benzene (10 mL, 0.05 M), then acetic acid (360 μL, 6.31 mmol,

12 equiv) was added and the reaction mixture was heated to 90 °C for 15 min. Compound

136

2-46 (130 mg, 0.526 mmol, 1 equiv) was added and stirred at 90 °C for 10 min, and then

the mixture was then cooled to room temperature. The solution was diluted with ethyl

acetate and poured over cold H2O (30 mL). The organic layer was washed with brine (3 ×

20 mL), dried over MgSO4 and concentrated via rotary evaporation. The crude product

was purified via flash column chromatography (gradient of 10% acetone in benzene

increasing to 25% acetone in benzene) to afford compound 2-47 (40 mg, 0.172 mmol,

14%). 1H NMR (360 MHz, (CDCl3): δ 7.34 (t, 2 H and br, 1 H), 7.25 (t, 1 H), 7.21 (d, 2

H), 6.78 (d, 1 H), 6.58 (d, 1 H), 4.74 (s, 2 H).

Procedures for the NMR Analysis of 2-23, 2-24, and 2-39:

Compound 2-23 (5 mg, 0.012 mmol, 1 equiv) was dissolved in CDCl3 (486 μL,

0.025M), and piperidine (1.2 μL, 0.012 mmol, 1 equiv) was added. The reaction was

monitored by integrating the furan benzylic peak (4.92 ppm) respect to tetramethylsilane

(TMS) (0.00 ppm, integrated to 1.00).

For the control study, compound 2-23 (5 mg, 0.012 mmol, 1 equiv) was dissolved

in CDCl3 (486 μL, 0.025M) and the benzylic peak was monitored with respect to TMS.

Compound 2-24 (5 mg, 0.018 mmol, 1 equiv) was dissolved in CDCl3 (486 μL,


monitored by integrating the furan benzylic peak (4.91 ppm) respect to tetramethylsilane

(0.00 ppm, integrated to 1.00).

Compound 2-39 (4.5 mg, 0.011 mmol, 1 equiv) was dissolved in CDCl3 (486 μL,


137

monitored by integrating the thiophene benzylic peak (5.11 ppm) respect to

tetramethylsilane (TMS) (0.00 ppm, integrated to 1.00).

Compound 2-39 (5 mg, 0.012 mmol, 1 equiv) was dissolved in a 10% solution of

piperidine in CDCl3 (486 μL, 0.025M). The reaction was monitored by integrating the

thiophene benzylic peak (5.11 ppm) respect to tetramethylsilane (TMS) (0.00 ppm,

integrated to 1.00).

For the control study, compound 2-39 (5 mg, 0.012 mmol, 1 equiv) was dissolved

in CDCl3 (486 μL, 0.025M) and the thiophene benzylic peak was monitored with respect

to TMS.

138



(3-11). Concentrated hydrochloric acid (HCl) (36% w/v, 72 mL) was added

dropwise to a solution of 2,6-dimethylphenol (3-10) (50.0 g, 409.2 mmol, 1 equiv) in

petroleum ether (ligroin) (204 mL, 2.0 M) and formaldehyde in water (37% w/v, 75 mL,

920.9 mmol, 2.25 equiv) over 10 min at room temperature. The reaction mixture was

stirred at room temperature for 16 h, after which the reaction mixture was poured into

500 mL of water. The white suspension was stirred at room temperature for 20 min. The

resulting white solid was collected on a Buchner funnel, washed with water (500 mL),

and dried at 70 °C under vacuum (~1 mmHg) overnight. The white solid was

recrystallized in hot dichloromethane to afford compound 3-11 as white crystals (37.4 g,

145.9 mmol, 71%). 1H NMR (400 MHz, (CD3)2CO): δ 7.00 (s, 2 H), 6.83 (s, 4 H) 3.70 (s,

2 H), 2.25 (s, 12 H); 13

C NMR (400 MHz, (CD3)2CO): δ 150.9, 132.9, 128.5, 123.3, 40.0,

15.7. The NMR data matches the known spectra for this compound.5,6

(3-12). Allyl bromide (3.4 mL, 39.01 mmol, 1 equiv) was added dropwise to a

stirred solution of 3-11 (10.0 g, 39.01 mmol, 1 equiv) and K2CO3 (6.47 g, 46.81 mmol,

1.2 equiv) in DMF (98 mL, 0.4 M). The reaction mixture was stirred at room temperature

139

for 22 h. Saturated ammonium chloride solution (200 mL) was added to the reaction

mixture and the mixture was extracted with ethyl acetate (4 × 150 mL). The combined

organic fractions were washed with brine (100 mL) and dried over MgSO4. The solids

were removed by filtration and the solution was concentrated via rotary evaporation. The

yellow residue was purified by flash column chromatography (gradient of 5% ethyl

acetate in hexanes increasing to 10% ethyl acetate in hexanes), affording compound 3-12

as a yellow oil (5.1 g, 17.48 mmol, 44%). 1H NMR (400 MHz, CDCl3): δ 6.86 (s, 2 H),

6.84 (s, 2 H), 6.14 (m, 1 H), 5.48 (dd, 1 H), 5.30 (dd, 1 H), 4.57 (s, 1 H), 4.32 (ddd, 2 H),

3.76 (s, 2 H), 2.31 (s, 6H), 2.28 (s, 6 H); 13

C NMR (400 MHz, CDCl3): δ 154.2, 150.5,

137.1, 134.3, 133.0, 130.8, 129.1, 129.0, 123.0, 117.1, 73.2, 40.6, 16.5, 16.0; The NMR

data matches the known spectra for this compound.6

(3-7). Silver oxide (7.99 g, 34.46 mmol, 2 equiv) was added to a solution of

compound 3-12 (5.10 g, 17.22 mmol, 1 equiv) in dichloromethane (172 mL, 0.1 M) and

the reaction mixture was stirred at room temperature for 11 h. The reaction mixture was

filtered to remove the silver oxide and the yellow solution was concentrated via rotary

evaporation. The resulting yellow solid was dried under vacuum overnight, affording

compound 3-7 as a bright yellow solid (5.01 g, 17.04 mmol, 99%). IR (cm-1): 2912,

2361, 1554, 980, 930; 1H NMR (400 MHz, CDCl3): δ 7.53 (s, 1 H), 7.12 (s, 2 H), 7.03 (s,

1 H), 6.99 (s, 1 H), 6.11 (m, 1 H), 5.46 (dd, 1 H), 5.29 (dd, 1 H), 4.35 (dd, 2 H), 2.31 (s, 6

H), 2.06 (s, 3 H), 2.04 (s, 3 H); 13

C NMR (400 MHz, CDCl3): δ 187.2, 157.4, 143.0,

139.1, 137.3, 135.3, 133.7, 131.7, 131.5, 131.3, 130.9, 117.6, 73.3, 17.0, 16.6, 16.2. The

NMR data matches the known spectra for this compound.6

140


(3-13). DIAD (3.85 mL, 19.5 mmol, 1.25 equiv) was added dropwise to a stirred

solution of 3-11 (4.0 g, 15.6 mmol, 1 equiv), triphenylphosphine (4.91 g, 18.72 mmol, 1.2

equiv) and 2-tridecen-1-ol (4.0 mL, 17.16 mmol, 1.1 equiv) in THF (31 mL, 0.5 M) at 0

oC. The reaction mixture was then warmed to room temperature overnight and stirred for

18 h. The mixture was concentrated via rotary evaporation and diluted in 50 mL EtOAc,

then washed with NH4Cl (2 × 50 mL) and brine (1 × 50 mL), dried over MgSO4 and

concentrated via rotary evaporation. The resulting yellow residue was purified via flash

column chromatography (gradient of 2% ethyl acetate in hexanes increasing to 10% ethyl

acetate in hexanes), affording compound 3-13 as a yellow oil (2.39 g, 5.48 mmol, 35%).

1H NMR (CDCl3, 400 MHz): δ 6.87 (s, 2H), 6.85 (s, 2H), 5.84 (m, 2H), 4.64 (s, 1H), 4.27

(d, 2H), 3.77 (s, 2H), 2.29 (s, 6H), 2.25 (s, 6H), 2.14 (q, 2H), 1.45 (br, 2 H), (br, 14H),

0.95 (t, 3H); 13

C NMR (400 MHz, CDCl3): δ 154.3, 150.5, 137.0, 135.3, 133.1, 130.9,

129.0, 125.8, 123.0, 73.3, 40.6, 32.4, 32.0, 29.7, 29.6, 29.4, 29.3, 29.1, 22.7, 16.6, 16.0,

14.2.

(3-8). Silver oxide (2.53 g mg, 10.9 mmol, 2 equiv) was added to a solution of

compound 3-13 (2.38 g, 5.45 mmol, 1 equiv) in dichloromethane (55 mL, 0.1 M) and the

141

reaction mixture was stirred at room temperature for 2 h. The reaction mixture was

filtered to remove the silver oxide and the yellow solution was concentrated via rotary

evaporation. The resulting yellow solid was dried under vacuum overnight, affording

compound 3-8 as a bright yellow solid (2.02 g, 4.65 mmol, 85%). 1H NMR (CDCl3, 400

MHz): δ 7.55 (s, 1H), 7.13 (s, 2H), 7.03 (s, 1H), 7.00 (s, 1H), 5.80 (m, 2H), 4.30 (d, 2H),

2.32 (s, 6H), 2.09 (s, 3H), 2.06 (s, 6H), 2.04 (m, 2 H), 1.40 (m, 2H), 1.26 (s, 16H), 0.89

(t, 3H); 13

C NMR (400 MHz, CDCl3): δ 187.2, 157.5, 143.1, 139.2, 137.2, 136.0, 135.3,

131.8, 131.5, 131.3, 131.2, 130.9, 125.2, 73.4, 32.3, 32.0, 29.6, 29.5, 29.4, 29.2, 29.0,

22.7, 17.0, 16.7, 16.2, 14.1


(3-15). DMSO (6.33 mL, 89.2 mmol, 2.5 equiv) was added to a stirred solution of

oxalyl chloride (4.28 mL, 49.9 mmol, 1.4 equiv) in dichloromethane (180 mL, 0.2 M) at

−78 °C. The mixture was stirred for 20 min before 4-pentyn-1-ol (3-14) (3.0 g,

35.7 mmol, 1 equiv) was slowly added. The mixture was stirred for a further 20 min

before triethylamine (30.6 mL, 178 mmol, 5 equiv) was added. This reaction mixture was

stirred for 30 min at −78 °C and then allowed to warm to room temperature and stirred

for a further 3 h. A solution of lithium chloride (2.72 g, 64.2 mmol, 1.8 equiv), triethyl

phosphonoacetate (12.7 mL, 64.2 mmol, 1.8 equiv) and 1,8-diazabicyclo[5,4,0]undec-7-

ene (8.82 mL, 64.2 mmol, 1.8 equiv) in MeCN (180 mL, 0.2 M) was then prepared and

142

stirred for 1 h. The Swern reaction solution was concentrated on high vacuum, then the

Horner–Wadsworth–Emmons solution in MeCN was added and the reaction mixture was

stirred at room temperature overnight. The reaction was quenched with a saturated

solution of ammonium chloride (100 mL) and concentrated to give an orange residue,

which was then extracted with diethyl ether (4 × 100 mL). The organic layers were

combined, dried (MgSO4), filtered and concentrated via rotary evaporation to give an oily

orange residue. Purification by flash column chromatography (10% Et2O in petroleum

ether) afforded 3-15 (3.52 g, 65%) as a yellow oil. δ1H NMR (CDCl3, 400 MHz): δ 6.90

(m, 1H), 5.80 (dd, 1H), 4.09 (q, 2H), 2.35 (t, 2H), 2.26 (q, 2H), 1.94 (s, 1H), 1.18 (t, 3H);

13C NMR (400 MHz, CDCl3): δ 166.1, 146.2, 122.4, 82.5, 69.4, 60.1, 30.9, 17.3, 14.1.

The NMR data matches the known spectra for this compound.7

(3-16). To a stirred solution of ethyl 3-15 (3.5 g, 22.0 mmol, 1 equiv) in Et2O

(110 mL, 0.2 M) at −78 oC was added DIBAL-H (1.0 M in hexanes) (50.6 mL, 50.6

mmol, 2.2 equiv). The mixture was stirred at −78 oC for 3 hours and then warmed to

room temperature overnight. The mixture was then cooled to 0 oC and

30 mL of saturated

NH4Cl was added to quench the reaction and stirred for 1 h. The suspension was then

filtered through Celite, dried over MgSO4 and concentrated via rotary evaporation. The

crude product was then purified via flash column chromatography (gradient of 20% Et2O

in petroleum ether increasing to 50% Et2O in petroleum ether) to afford 3-16 as a clear

liquid (2.14 g, 14.06 mmol, 85%). 1H NMR (CDCl3, 400 MHz): δ 5.70 (m, 2H), 4.07 (d,

2H), 2.25 (m, 4 H), 1.99 (s, 1 H), 1.95 (s, 1 H) ; 13

C NMR (400 MHz, CDCl3): δ 130.5,

130.3, 83.8, 68.8, 63.2, 31.1, 18.4. The NMR data matches the known spectra for this

compound.7

143


(3-17). DIAD (4.65 mL, 23.60 mmol, 1.25 equiv) was added dropwise to a stirred

solution of 3-11 (4.84 g, 18.88 mmol, 1 equiv), triphenylphosphine (5.94 g, 22.66 mmol,

1.2 equiv) and 3-16 (2.08 g, 18.88 mmol, 1.0 equiv) in THF (45 mL, 0.5 M) at 0 oC. The

reaction mixture was then warmed to room temperature overnight and stirred for 18 h.

The mixture was concentrated via rotary evaporation and diluted in 50 mL EtOAc, then

washed with NH4Cl (2 × 30 mL) and brine (1 × 30 mL), dried over MgSO4 and

concentrated via rotary evaporation. The resulting yellow residue was purified via flash

column chromatography (gradient of 5% ethyl acetate in hexanes increasing to 20% ethyl

acetate in hexanes), affording compound 3-17 as a yellow oil (2.23 g, 6.41 mmol, 34%).

1H NMR (CDCl3, 400 MHz): δ 6.86 (s, 2 H), 6.84 (s, 2 H), 5.89 (dd, 2 H), 4.61 (s, 1 H),

4.29 (d, 2 H), 3.76 (s, 2 H), 2.37 (m, 4 H), 2.34 (s, 6 H), 2.28 (s, 6 H), 2.02 (s, 1 H); 13

C

NMR (400 MHz, CDCl3): δ 154.2, 150.5, 137.1, 133.1, 132.4, 130.8, 129.0, 127.4, 123.1,

83.8, 72.6, 68.9, 40.6, 31.3, 18.4, 16.6, 16.0.

(3-9). To a stirred solution of (3-17) in diethyl ether (120 mL, 0.05 M) was added

slowly a solution of potassium ferricyanide (7.76 g, 23.56 mmol, 4 equiv) and KOH (1.37

g, 24.74 mmol, 4.2 equiv) in water (25 mL, 0.25 M). The mixture was stirred at room

144

temperature for 2 hours. The organic layer was removed from the mixture, the resulting

aqueous layer was extracted with diethyl ether (3 × 50) and the combined organic

fractions were dried over MgSO4. The solution was then concentrated by rotary

evaporation to afford compound 3-9 as a bright yellow solid (1.90 g, 5.49, 93%). 1H NMR

(CDCl3, 400 MHz): δ 7.55 (s, 1 H), 7.14 (s, 2 H), 7.06 (s, 1 H), 7.03 (s, 1 H), 5.89 (dd, 2

H), 4.33 (d, 2 H), 2.33 (m, 4 H), 2.33 (s, 6 H), 2.08 (s, 3 H), 2.06 (s, 3 H), 1.98 (s, 1 H) ;

13C NMR (400 MHz, CDCl3): δ 187.7, 157.8, 143.5, 139.6, 137.7, 135.7, 133.4, 132.2,

131.9, 131.7, 131.3, 127.3, 84.0, 73.4, 69.3, 31.6, 18.7, 17.4, 17.1, 16.7.


(3-22). To a stirred solution of triethylene glycol 2-bromoethyl methyl ether (3-

21) (2.0 g, 7.38 mmol, 1 equiv) in DMSO (37 mL, 0.2 M) was added sodium azide (960

mg, 14.75 mmol, 2 equiv) at room temperature. The mixture was stirred for 12 hours at

room temperature. The reaction mixture was then extracted with diethyl ether (30 mL),

and the organic layer was removed. The DMSO layer was then diluted with water (40

mL), extracted with diethyl ether (50 mL × 3), then the organic fractions were combined,

dried over MgSO4 and concentrated by rotary evaporation. The resulting liquid was then

dried on high vacuum for 24 hours to afford compound 3-22 as a clear oil (1.62 g, 6.95

mmol, 94%). 1H NMR (CDCl3, 400 MHz): δ 3.60 (m, 12 H), 3.50 (t, 2 H), 3.34 (m, 5 H) ;

145

13C NMR (400 MHz, CDCl3): δ 71.8, 70.6, 70.6, 70.5, 70.4, 70.3, 69.9, 58.8, 50.5, 40.9.

The NMR data matches the known spectra for this compound.8

Figure 5-14. Synthetic scheme for polymer 3-4.

(3-4). Compound 3-7 (500 mg, 1.70 mmol, 1 equiv) was added to a flame-dried

10 mL round bottom flask with an egg-shaped stir bar, dried under vacuum and

backfilled with an argon atmosphere. Anhydrous DCM (1.7 mL, 1 M) was added to the

flask, which was cooled to –20 oC in an iPrOH bath chilled by a VWR Refrigerated

Circulating Bath. A stock solution of MeOH (138 µL, 3.41 mmol) in 1 mL anhydrous

DCM was prepared and 10 µL of this solution (1.38 µL, .034 mmol, 0.02 equiv) were

added dropwise to the reaction mixture, immediately followed by addition of the P1-t-Bu

phosphazene base (10.4 µL, .034 mmol, .02 equiv). The reaction mixture was stirred at –

20 oC for 1 h and quenched with acetic anhydride (800 µL, 8.50 mmol, 5 equiv) that was

previously mixed with K2CO3 to remove trace amounts of AcOH. After 1 h, the

circulating bath was turned off and the reaction mixture slowly warmed to room

temperature, stirring for 12 h. The polymer was precipitated into MeOH (40 mL) at 0 oC

146

and allowed to sit for 10 min. The solvent was drained using a polymer washer. The

polymer was then redissolved in DCM, and 5 drops of DBU were added and stirred at

room temperature for 1 h to remove any un-endcapped polymer from the solution. The

precipitation process described previously was repeated twice more. The resulting

polymer 3-4 was isolated as a white solid (425 mg, 85%) and was dried under vacuum for

24 h. Mn = 72.8 kDa, Mw = 111.5 kDa, PDI = 1.53. 1H NMR (400 MHz, CDCl3): δ6.93

(br, 4 H), 6.10 (br, 1 H), 5.55 (br, 1 H), 5.44 (br, 1 H), 5.26 (br, 1 H), 4.31 (br, 2 H), 2.24

(br, 6 H), 1.86 (br, 6 H). The NMR data matches the known spectra for this compound.9

Figure 5-15. Synthesis of polymer 3-5.





Circulating Bath. A stock solution of MeOH (37 µL, 9.2 mmol) in 1 mL anhydrous DCM

was prepared and 10 µL of this solution (.37 µL, 9.2 μmol, 0.02 equiv) were added

147

dropwise to the reaction mixture, immediately followed by addition of the P1-t-Bu

phosphazene ase (2.9 µL, 9.2 μmol, .02 equiv). The reaction mixture was stirred at –20

oC for 1 h and quenched with acetic anhydride (220 µL, 2.30 mmol, 5 equiv) that was

previously mixed with K2CO3 to remove trace amounts of AcOH. After 1 h, the







polymer 3-5 was isolated as a white solid (122 mg, 61%) and was dried under vacuum for

24 h. Mn = 31.2 kDa, Mw = 45.9 kDa, PDI = 1.47. 1H NMR (400 MHz, CDCl3): δ 6.92

(br, 4 H), 5.79 (br, 2 H), 5.56 (br, 1 H), 4.25 (br, 2 H), 2.24 (br, 6 H), 2.10 (br, 2 H), 1.87

(br, 6 H), 0.91 (br, 3 H).

148






Circulating Bath. A stock solution of MeOH (140 µL, 34.7 mmol) in 1 mL anhydrous

DCM was prepared and a 10 µL aliquot of this solution (1.4 µL, 34.7 μmol, 0.04 equiv)

were added dropwise to the reaction mixture, immediately followed by addition of the P1-

t-Bu phosphazene ase (10.6 µL, 34.7 μmol, .04 equiv). The reaction mixture was stirred

at –20 oC for 1 h and quenched with acetic anhydride (410 µL, 4.33 mmol, 5 equiv) that

was previously mixed with K2CO3 to remove trace amounts of AcOH. After 1 h, the





149



polymer 3-18 was isolated as a white solid (246 mg, 82%) and was dried under vacuum

for 24 h. Mn Mn = 38.4 kDa, Mw = 45.0 kDa, PDI = 1.17. 1H NMR (400 MHz, CDCl3): δ

6.90 (br, 4 H), 5.84 (br, 2 H), 5.53 (br, 1 H), 4.26 (br, 2 H), 2.30 (br, 4 H), 2.22 (br, 6 H),

1.96 (br, 1 H), 1.86 (br, 6 H).


(3-6). To a stirred solution of polymer 3-18 (200 mg, 0.58 mmol, 1 equiv) and

triethylene glycol 2-azidoethyl methyl ether (148 mg, 0.63 mmol, 1.1 equiv) in THF (2.9

mL, 0.2 M) was added a suspension of copper(I) iodide (22 mg, 0.11 mmol, 0.2 equiv)

and N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (24 μL, 0.11 mmol, 0.2 equiv) in THF

(2.9 mL, 0.2 M). The reaction was stirred vigorously with an egg-shaped stir bar

overnight at 60 oC. The mixture was then concentrated using rotary evaporation and

rediluted with DCM (50 mL). The organic layer was washed with sat. NH4Cl (30 mL ×

2) and brine (30 mL × 1), then dried over MgSO4 and concentrated via rotary

150

evaporation. The resulting crude oil was dissolved in a small amount of DCM, then

precipitated into cold Et2O (50 mL). The precipitate was filtered out of the solution, then

dissolved in DCM and precipitated into cold Et2O twice more. Resulting polymer 3-6 was

isolated as a white/tan solid (283 mg, 84%) and was dried under vacuum for 24 h. Mn =

70.1, Mw = 87.7 kDa, PDI = 1.25. 1H NMR (400 MHz, CDCl3): δ 7.46 (s, 1 H), 6.92 (s, 1

H), 6.88 (s, 2 H), 6.84 (s, 1 H), 5.84 (m, 2 H), 5.50 (s, 1 H), 4.48 (t, 2H), 4.20 (s, 2 H),

3.82 (t, 2 H), 3.58 (m, 10 H), 3.50 (t, 2 H), 3.33 (s, 3 H), 2.81 (t, 2 H), 2.47 (t, 2 H), 2.19

(s, 3 H), 2.17 (s, 3 H), 1.84 (s, 3 H), 1.82 (s , 3 H).

Solution Phase Depolymerization in Response to palladium:

For polymer 3-4 (Mn = 72.8 kDa), a 34 μM solution of

Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) in THF (2.0 mL) was added to a

solution of polymer 3-4 (5.0 mg, 17 µmol, 1 equiv) and 85 mM 1,8-diazabicycloundec-7-

ene (DBU) in tetrahydrofuran (1 mL). The solution was stirred in a 2 mL shorty vial,

syringed filtered, and injected into the GPC. (Figure 3-15).

For polymer 3-6 (Mn = 70.1 kDa), a 34 μM solution of

Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) in THF (2.0 mL) was added to a

solution of polymer 3-6 (5.0 mg, 17 µmol, 1 equiv) and 85 mM 1,8-diazabicycloundec-7-

ene (DBU) in tetrahydrofuran (1 mL). The solution was stirred in a 2 mL shorty vial,

syringed filtered, and injected into the GPC. (Figure 3-15).

151

Solution Phase Control Study:

Polymers 3-4 (5 mg, Mn = 72.8 kDa), and 3-6 (5 mg, Mn = 70.1 kDa) were

dissolved in 85 mM solutions of DBU in THF (2.0 mL). The solutions were stirred in a 2

mL shorty vial, syringed filtered, and injected into the GPC for analysis (Figure 3-16).

Solid-State Depolymerization in Response to Pd(0):

Fabrication of Polymer Discs:

Silicon molds were prepared on a microscope glass slide. A solution of polymer

in anhydrous toluene (100 mg/mL) with dibutyl phthalate (20% wt.) was prepared. Using

a 100-µL syringe, the solution was deposited dropwise into the silicon mold. The solution

was left to dry overnight and the dried disc was removed from the mold using an X-Acto

knife and a razor blade. The disc was dried under high vacuum (~1 mmHg) for 24 h.

Experimental Procedure for Testing the Polymer Disc When Exposed to Pd(0):

Polymer discs were prepared from polymers 3-4, 3-5, and 3-6. In a 20-mL

scintillation glass vial, the polymer disc was suspended in water (19 mL). 1,8-

diazabicyclo-7-undecene (100 µL, 0.67 mmol) was added dropwise to the suspension,

followed by a solution of Pd(PPh3)4 in tetrahydrofuran (17 mmol in 1 mL). The reaction

progress was monitored by photography (Figure 3-17).

LCMS Analysis of Products from the Depolymerization Reaction of Polymer 3-6:

To evaluate the byproducts that are generated from the solid-state

depolymerization reaction of polymer 3-6, an experiment analogous to the solid-state

152

depolymerization study outlined above was prepared with a 9:1 H2O-THF solvent

mixture. Following 12 hours, an aliquot was removed from the solution surrounding the

solid-state polymer disc. LCMS analysis of the reaction mixture showed two peaks with

masses corresponding to the expected masses of the deprotected small molecule

monomer (3-19) (M + H+ = 255.1) as well as the PEG-4 monomer (3-20) (M + H

+ =

580.2) (Figure 3-21).

Contact Angle Measurement on Polymers

After spin-coating on glass substrate, contact angles from polymer films 3-4, 3-5,

and 3-6 were measured with a 5 μL droplet of water. Three samples were measured for

each polymer after drying in vacuo. The average and standard deviation for each contact

angle were calculated.

SEM Images of Polymer Discs Prepared from Polymers 3-4, 3-5, and 3-6

A surface morphology of each polymer disc from polymers 3-4, 3-5, and 3-6 was

characterized by SEM imaging on a Zeiss Sigma FE-SEM (Figure 3-23).

153


General Procedure for GPC Sonication Experiments

Solutions of polymers 4-1, 4-2, and 4-3 in THF (15 mg/15 mL) were transferred

to a Suslick cell, each arm was sealed with a rubber cap, and the cell was affixed to the

sonication apparatus with the cell submerged in a water/ice bath. The probe sonicator was

programmed at 30% amplification with a pulse sequence of 1 sec on, 9 sec off. At

predetermined time points, 150 μL of the polymer solution was removed, syringe filtered,

and injected directly into the GPC for analysis. The refractive index (RI) signal was

exported and graphed vs. time to create the polymer data graphs.

154

5.7 References

(1) Pangborn, A. B.; Giardello, M. a.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.

Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15

(5), 1518–1520.

(2) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals (Sixth

Edition); 2009.

(3) Clark, W.; Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for

Preparative Separations with Moderate Resolution. J. Org. Chem. 1978, 43 (14),

2923–2925.

(4) Mutter, M.; Bellof, D. 232. A New Base-Labile Anchoring Group for Polymer-

Supported Peptide Synthesis. Helv. Chim. Acta 1984, 67 (1984), 2009–2016.

(5) Deota, P. T.; Parmar, H. S.; Valodkar, V. B.; Upadhyay, P. R.; Sahoo, S. P.

Oxidative Acetylation of Tetramethyl Bisphenol F. Synth. Commun. 2006, 36 (5),

673–678.

(6) Yeung, K.; Kim, H.; Mohapatra, H.; Phillips, S. T. Surface-Accessible Detection

Units in Self-Immolative Polymers Enable Translation of Selective Molecular

Detection Events into Amplified Responses in Macroscopic, Solid-State Plastics.

J. Am. Chem. Soc. 2015, 137 (16), 5324–5327.

(7) Grafton, M. W.; Johnson, S. A.; Farrugia, L. J.; Sutherland, A. Diastereoselective

Synthesis of Highly Substituted Polycyclic Scaffolds via a One-Pot Four-Step

Tandem Catalytic Process. Tetrahedron. 2014, pp 7133–7141.

(8) Zhang, Q.; Chang, C. W. T. Divergent and Facile Lewis Acid-Mediated Synthesis

of N-Alkyl 2-Aminomethylene-1,3-Indanediones and 2-Alkylamino-1,4-

Naphthoquinones. Tetrahedron Lett. 2015, 56 (7), 893–896.

(9) Yeung, K. Stimuli-Responsive Reagents for the Detection Glycosidases, The

Pennsylvania State University, 2014.

155

Appendix A

NMR Spectra

Chapter 1 NMR Spectra:

1H NMR of compound 1-19.

156

13

C NMR of compound 1-19.

157


158


159

13


160


161

13


162


163


164


165


166


167


168


169



170


171


172


173


174


175

1H NMR spectrum of 2-30.

176


177


178


179


180


181


182


183


184


185


186


187


188


189


190


191


192



193

13

C NMR spectrum of 3-11.

194


195

13


196


197

13


198


199

13


200


201

13


202


203

13


204


205

13


206


207

13


208


209

13


210


211


212


213


214


215

13


216

Appendix B

Data Tables for Kinetics Experiments

Data for Chapter 1:

The data tables below are labeled with a letter corresponding to each product within the

autocatalytic reaction of each reagent. The internal standard is abbreviated “IS”.

1-15:

1-16:

1-17:

217

LCMS data for mechanistic studies of 1-15, 1-16, and 1-17:

(1-15).

(1-16).

time (h) A int B int IS int

0 5162 0 2345

1 6353 349 3030

2 5376 470 2701

3 5063 722 2804

4 4754 1187 2898

5 3896 1507 2915

6 3232 2168 3245

7 2569 2540 3331

8 1939 2802 3436

9 1434 2862 3413

10 972 2786 3396

11 759 2920 3466

12 558 2769 3444

13 314 3810 4361

time (h) A int B int C int IS int

0 1375 6557.7 0 0

1 1462.6 6458.1 312.5 0

2 1565.8 6235.3 791.8 0

3 1471.9 4877.4 1537.7 120.1

4 1530.2 3275.3 2522.6 496.7

5 1596.9 1975.1 2728.3 1021.6

6 1687.3 962 2334.5 1629.4

7 1676.8 465 1582.8 1732.3

8 1701 185.3 1010.2 1749.6

9 1799.7 91 619.6 1543.8

10 1817.5 0 361.2 1308.9

218

(1-17).

UV/Vis data for kinetic studies (100 mM)

(1-15).

time (h) A int B int C int D int IS int

0 - - - - -

1 16131.6 4403.8 460.1 0 3551.6

2 8657.7 7642 2355.1 283.1 3449.9

3 3487.6 7330.4 5631.8 1464.3 4020.5

4 643.9 2660.1 4605.4 2635.4 3790.7

5 110.1 729.5 2363.3 2562.6 3839.1

6 0 382.3 851.7 1903.8 4323.3

7 0 0 420.9 1426.9 4856.1

time (h) A (Avg) St Dev

0 0.051 0.002

1 0.093 0.006

2 0.146 0.008

3 0.234 0.002

4 0.338 0.018

5 0.452 0.003

6 0.600 0.019

7 0.715 0.006

8 0.777 0.030

9 0.835 0.011

10 0.861 0.010

11 0.875 0.046

12 0.910 0.013

13 0.917 0.030


0 0.000 0.002

1 0.049 0.006

2 0.110 0.008

3 0.213 0.002

4 0.334 0.018

5 0.467 0.003

6 0.639 0.019

7 0.773 0.006

8 0.845 0.030

9 0.912 0.011

10 0.943 0.010

11 0.959 0.046

12 1.000 0.013

13 1.008 0.030

Experimental Data Normalized Data

219

(1-16).

(1-17).

(1-26).


0 0.063 0.001

1 0.155 0.018

2 0.313 0.017

3 0.629 0.021

4 1.032 0.015

5 1.378 0.061

6 1.556 0.037

7 1.583 0.065

8 1.541 0.079

Experimental Data


0 0.000 0.001

1 0.060 0.018

2 0.165 0.017

3 0.373 0.021

4 0.638 0.015

5 0.865 0.061

6 0.982 0.037

7 1.000 0.065

8 0.972 0.079

Normalized Data

Experimental Data


0 0.115 0.068

1 0.251 0.055

2 0.681 0.031

3 1.261 0.039

4 1.655 0.096

5 1.823 0.033

6 1.800 0.067


0 0.000 0.068

1 0.080 0.055

2 0.331 0.031

3 0.671 0.039

4 0.902 0.096

5 1.000 0.033

6 0.986 0.067

Normalized Data


0 0.796 0.030

2 0.906 0.014

3 0.954 0.022

4 1.078 0.023

5 1.131 0.028

6 1.330 0.017

7 1.389 0.089

8 1.518 0.098

9 1.564 0.154

10 1.588 0.082

11 1.638 0.083

12 1.639 0.095

Experimental Data


0 0.000 0.030

2 0.131 0.014

3 0.187 0.022

4 0.335 0.023

5 0.398 0.028

6 0.633 0.017

7 0.704 0.089

8 0.857 0.098

9 0.912 0.154

10 0.940 0.082

11 0.999 0.083

12 1.000 0.095

Normalized Data

220

Data for Chapter 2:

NMR Data for kinetics studies of 2-23:

(2-23): Response to 1 equiv piperidine in CDCl3.

Integration is recorded through integrating the furan benzylic peak (4.92 ppm) w/r/t TMS.

(2-23): Control study in CDCl3


time (h) Integration Reagent

remaining

0 1.14 100.0%

0.25 1.06 93.0%

0.5 0.97 85.1%

0.75 0.91 79.8%

1 0.86 75.4%

1.5 0.74 64.9%

2 0.66 57.9%

3 0.54 47.4%

4 0.47 41.2%

6 0.34 29.8%

8 0.27 23.7%

10 0.2 17.5%

18 0.1 8.8%

27 0.05 4.4%

36 0.02 1.8%


remaining

0 1.1 100.0%

1 1.1 100.0%

2 1.08 98.2%

4 1.02 92.7%

8 0.92 83.6%

18 0.44 40.0%

27 0.22 20.0%

36 0.07 6.4%

221


(2-24): Response to 1 equiv piperidine in CDCl3


(2-24): Control study in CDCl3



remaining

0 0.99 100.0%

1 0.87 87.9%

2 0.65 65.7%

4 0.47 47.5%

6 0.37 37.4%

8 0.31 31.3%

10 0.26 26.3%

12 0.21 21.2%

24 0.12 12.1%

28 0.09 9.1%

36 0.07 7.1%

48 0.06 6.1%

132 0.02 2.3%


remaining

0 0.99 100.0%

1 0.98 99.0%

2 0.94 94.9%

4 0.91 91.9%

6 0.88 88.9%

8 0.84 84.8%

10 0.81 81.8%

12 0.76 76.8%

24 0.66 66.7%

28 0.6 60.6%

36 0.57 57.6%

48 0.46 46.5%

132 0.12 12.2%

222


(2-39): Response to 1 equiv piperidine in CDCl3



remaining

5 1.1 100.0%

30 1.1 100.0%

60 1.08 98.2%

150 1.04 94.5%

240 0.98 89.1%

360 0.94 85.5%

480 0.87 79.1%

600 0.84 76.4%

720 0.81 73.6%

840 0.75 68.2%

1260 0.68 61.8%

1740 0.6 54.5%

2280 0.5 45.5%

2820 0.44 40.0%

4320 0.33 30.0%

223

(2-39): Response to 5% piperidine in CDCl3

a) Integration recorded by integrating the furan benzylic peak (5.11 ppm) w/r/t TMS.

b) Integration recorded by integrating the triplet peak corresponding to the 3-position of

free phenol (7.20 ppm) w/r/t TMS.

a) b)


remaining

0.08 1.2 100.0%

0.17 1.15 95.8%

0.5 1.08 90.0%

1 0.93 77.5%

1.5 0.71 59.2%

2 0.63 52.5%

2.5 0.55 45.8%

3 0.47 39.2%

3.5 0.39 32.5%

4 0.34 28.3%

5.5 0.23 20.0%

6.5 0.14 13.0%

12.5 0.02 2.2%

14.5 0.01 1.4%

time (h) Integration Phenol

released

0.08 0 0.0%

0.17 0.03 2.5%

0.5 0.07 5.9%

1 0.11 9.3%

1.5 0.14 11.9%

2 0.19 16.1%

2.5 0.22 18.6%

3 0.2 16.9%

3.5 0.24 20.3%

4 0.26 22.0%

5.5 0.33 28.0%

6.5 0.37 31.4%

12.5 0.58 49.2%

14.5 0.65 55.1%

16.5 0.76 64.4%

18.5 0.81 68.6%

20.5 0.86 72.9%

22.5 0.93 78.8%

24.5 0.96 81.4%

26.5 1 84.7%

28.5 1.05 89.0%

39 1.16 98.3%

49 1.18 100.0%

224

(2-39): Response to 10% piperidine in CDCl3

a) Integration recorded by integrating the furan benzylic peak (5.11 ppm) w/r/t TMS.

b) Integration recorded by integrating the triplet peak corresponding to the 3-position of

free phenol (7.20 ppm) w/r/t TMS.

a) b)


remaining

0.08 1.38 100.0%

0.17 1.3 94.2%

0.25 1.12 81.2%

0.33 0.97 70.3%

0.50 0.77 55.8%

0.75 0.65 47.1%

1.00 0.57 41.3%

1.25 0.52 37.7%

1.50 0.31 22.5%

1.75 0.27 19.6%

2.00 0.19 13.8%

2.25 0.15 10.9%

2.50 0.13 9.4%

2.75 0.07 5.1%

3.00 0.04 2.9%

5.00 0.01 0.7%

time (h) Integration

Phenol formed

0.08 0 0.0%

0.17 0.03 2.5%

0.50 0.07 5.9%

1.00 0.11 9.3%

1.50 0.14 11.9%

2.00 0.19 16.1%

2.50 0.22 18.6%

3.00 0.2 16.9%

3.50 0.24 20.3%

4.00 0.26 22.0%

5.50 0.33 28.0%

6.50 0.37 31.4%

12.50 0.58 49.2%

14.50 0.65 55.1%

16.50 0.76 64.4%

18.50 0.81 68.6%

20.50 0.86 72.9%

22.50 0.93 78.8%

24.50 0.96 81.4%

26.50 1 84.7%

28.50 1.05 89.0%

39.00 1.16 98.3%

49.00 1.18 100.0%

225

Data for Chapter 3:

Contact Angle Data

AFM Data

3-4 3-5 3-6

1 93.0 95.7 69.7

2 95.3 95.7 69.5

3 93.3 97.5 70.0

Average (°) 93.9 96.3 69.7

Standard deviation (°)

1.3 1.0 0.3

3-4 3-5 3-6

1 1375.0 26.3 30.7

2 1341.0 29.3 33.7

3 1194.0 32.8 33.6

Average (MPa) 1303.3 29.5 32.7

Standard deviation (MPa)

96.2 3.3 1.7

226

VITA

Travis J. Cordes

Travis J. Cordes was born and raised in Omaha, Nebraska and graduated from

Ralston High School in 2006. He then attended Iowa State University, and in 2008 he

began his undergraduate research career with Professor Don Beitz in the Department of

Animal Science. Working with Dr. Jon Schoonmaker, he did chemical analysis of beef

and milk samples to study the correlation between the diets of farm animals and the

healthfulness of the food products they provide. In 2009 he joined the lab of Professor

George Kraus in the Department of Chemistry, where he participated in research within

the National Science Foundation Engineering Research Center for Biorenewable

Chemicals. Here, he applied chemical catalysis to develop new strategies for converting

biomass into relevant industrial chemicals. For his work at Iowa State, he was twice

awarded the Glen A. Russell Memorial Scholarship for excellence in organic chemistry.

He graduated cum laude in 2010 with a B.S. degree in chemistry and a minor in

mathematics. Upon graduation, he enrolled as a graduate student in the Department of

Chemistry at Penn State University and joined the la of Professor Scott Phillips. Travis’

graduate research spanned a variety of methods for signal amplification, including

autocatalysis, depolymerizable polymers, and mechanoresponsive materials. In the fall of

2016, he will begin a career at PPG Industries in Cincinnati, Ohio as a Polymer

Development Chemist in the Packaging Coatings division.

Documents

DESIGN AND SYNTHESIS STRATEGIES FOR SMALL MOLECULE …