CATALYST, MECHANISM, and REACTION DEVELOPMENT in ACRIDINIUM and FLAVIN PHOTOREDOX CATALYSIS Ian Andrew Mackenzie a Dissertation

CATALYST, MECHANISM, AND REACTION DEVELOPMENT IN ACRIDINIUM AND FLAVIN PHOTOREDOX CATALYSIS

Ian Andrew MacKenzie

A dissertation submitted to the faculty of The University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry.

Chapel Hill 2019

Approved by:

David A. Nicewicz

Simon J. Meek

Sidney M. Wilkerson-Hill

Michel R. Gagné

Gerald J. Meyer

ABSTRACT

Ian Andrew MacKenzie: Catalyst, Mechanism, and Reaction Development in Acridinium and Flavin Photoredox Catalysis (Under the direction of David A. Nicewicz)

The field of photoredox catalysis has grown tremendously over the past decade. This is due primarily to the wealth of new reactivity made accessible by open shell intermediates generated upon single electron transfer (SET). However, the cost of photoredox catalysts in some cases remains undesirably high. Additionally, the most well studied catalytic systems are based on precious metal photosensitizers while fully organic catalysts are significantly less developed.

In the work described herein, we report on our efforts to address, in part, both of these challenges.

Acridinium dyes are a class of highly oxidizing organic photoredox catalysts. Through simple design, we have synthesized a series of acridinium catalysts bearing siloxane anchoring groups for attachment onto high surface area metal oxides with the goal of recyclable catalysis.

Surface loading and photostability of the catalysts are reported. High conversion for a photoredox mediated Newman-Kwart rearrangement could be achieved for one substrate with catalyst loadings less than 0.1%. Reactivity was not general and time-resolved emission studies revealed a high degree of catalyst excited state quenching upon surface attachment. Further photophysical investigations indicate an interesting and rare hole injection process as partially responsible for the observed excited state quenching.

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Immobilization of an organic flavin photocatalyst on high surface area metal oxides resulted in excellent catalytic activity. High yields for benzylic oxidation or oxygenation of a variety of alkyl benzene substrates were achieved with catalyst loadings less than 0.02%.

Finally, in an effort to further characterize the acridinium class of photoredox catalysts, we investigated the photophysical properties of the one electron reduced acridyl radical.

Examination of the excited state topology revealed two distinct emissive excited states, tentatively assigned as a locally excited doublet (D1) state and a twisted intramolecular charge transfer (TICT) state. Both excited states were found to be extremely reducing with the oxidation potential of the TICT state exceeding that of lithium. Application of photoexcited acridyl radical in catalysis was achieved in the reductive dehalogenation of electron rich aryl bromides and chlorides. Selective C–O cleavage of aryl methane sulfonates was also demonstrated.

ACKNOWLEDGEMENTS

It is difficult to know even where to begin in my gratitude and acknowledgements. I have deeply enjoyed my time in graduate school and have been incredibly blessed by so many people during my time here in Chapel Hill.

First, I sincerely want to thank Dave for the opportunity to work in your lab and learn from you over the past four years. I am extremely grateful for your interest and willingness to take me on as a second year student switching from a different lab. I have grown tremendously as a scientist during this time and sincerely appreciate your guidance and flexibility.

I want to thank my friends and coworkers in lab, past and present. You have brought laughter and a cheerful attitude to a difficult field of study. Your companionship and creative ideas have been much enjoyed. In particular, I would especially like to thank Nate Romero and

Andrew Perkowski. Both of you took it upon yourselves to patiently instruct me at the bench and at the whiteboard. I am incredibly grateful for your investment in me and your continual support in my journey.

To all of the many collaborators inside and outside the department I am grateful. In particular, I would mention Prateek Dongare and Degao Wang for their assistance on solid supported catalyst projects. I certainly could never have gotten started, or continued, without your help.

Christian fellowship within the department has been a great source of strength for me.

Kevin Olson, your friendship was a continual refreshment. Thank you for standing by me when life was hard. Kyle Brennaman, thank you for your honesty and for your deep, deep desire to be

v in communion with God. Your friendship, your prayers, and your struggles have been a reminder of God’s presence and love.

Outside chemistry, many others have lifted me up. Glynis Cowell, thank you for being a faithful servant of God to those around you. I am so grateful for you and for the interdepartmental fellowship group that you started. Jay and Anne Summach, thank you for loving me like your own child. Paul and Judy Gerritson, you have overwhelmed me with your love and generosity. Thank you for your continued friendship.

Carolina baseball will be greatly missed. I have had a lot of good times at Boshamer

Stadium. Go Heels!

The music of Andrew Peterson has touched my soul.

I am so grateful also for my children who were born during this time. Catherine, you are a daily joy and a wonderful little helper. I am deeply proud of you and love you dearly.

Charlotte, you continually bring a smile to my face. Even at 3am when you should be asleep, and

I would much prefer to be, your little face is so cute and innocent. Anne, I miss you deeply and I will always love you. I trust you to the arms of Jesus.

To my parents, who will forever be Mama and Papa to me, thank you. Your love made space for me in this world and brought joy with it. Thank you for all that you have given me and for the example of Christ’s love that you continue to display.

My dearest Sarah, I cannot adequately express my gratitude or my love for you. I am awed by your love and continual support. I have never and will never deserve you, but I hope that you know in some small way how great a blessing you are and how much I love you. You are my princess.

Finally, though certainly not least, I am grateful to God. Everything that I have and am comes from You. Thank You for carrying me and for continually showing me Your love in big and little ways. Thank You for not letting go of me, ever. May You alone be honored, praised, and glorified through my work and my life.

Soli Deo Gloria.

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To my wife, Sarah

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TABLE OF CONTENTS

LIST OF FIGURES ...... xiii LIST OF SCHEMES ...... xvii LIST OF CHARTS ...... xix LIST OF TABLES ...... xx LIST OF ABBREVIATIONS AND SYMBOLS ...... xxi CHAPTER 1: INTRODUCTION TO ACRIDINIUM AND FLAVIN VISIBLE LIGHT PHOTOREDOX CATALYSIS ...... 1 1.1 Introduction ...... 1 1.2 Fundamental principles of photoredox catalysis...... 2 1.2.1 Photophysical processes...... 2 1.2.2 Thermodynamics of Photoinduced Electron Transfer (PET) ...... 3 1.2.3 Example reactions ...... 6 1.3 Development of Acridinium and Flavin Photoredox Catalysts ...... 8 1.3.1 Evolution of Acridinium Photoredox Catalysis ...... 8 1.3.2 The Development of Synthetic Flavin Photoredox Catalysis ...... 11 1.4 Conclusions ...... 14 CHAPTER 2: PROGRESS TOWARDS DEVELOPMENT OF SOLID-SUPPORTED ACRIDINIUM PHOTOCATALYSTS ...... 15 2.1 Introduction ...... 15 2.2 Results and Discussion ...... 16 2.2.1 Synthetic Efforts towards Acridiniums Functionalized with a Siloxane Anchoring Group ...... 16 2.2.2 Loading and “Dark” Stability ...... 18 2.2.3 Initial Photostability Results ...... 20

2.2.4 Improved Photostability ...... 21 2.2.5 Counterion Identity and Catalyst Degradation ...... 23 2.2.6 Catalytic Activity of Surface-Tethered Acridinium Catalysts ...... 25 2.2.7 Photophysical Investigations of Solid-Supported Catalysts ...... 27 2.3 Conclusions ...... 35 2.4 Future Work ...... 35 2.5 Acknowledgements ...... 36 CHAPTER 3: OXIDATION OF ALKYL BENZENES BY A FLAVIN PHOTO- OXIDATION CATALYST ON NANOSTRUCTURED METAL-OXIDE FILMS ...... 37 3.1 Introduction ...... 37 3.2 Results and Discussion ...... 42 3.3 Conclusions ...... 47 3.4 Methods...... 47 3.5 Acknowledgements ...... 48 CHAPTER 4: STRONGER THAN LITHIUM: PHOTOEXCITED ACRIDYL RADICAL AS A SUPER-REDUCTANT FOR SINGLE ELECTRON REDOX CHEMISTRY ...... 49 4.1 Introduction ...... 49 4.2 Results and Discussion ...... 51 4.3 Conclusions ...... 65 4.4 Future Work ...... 66 4.5 Associated Content ...... 66 4.6 Acknowledgement ...... 66 APPENDIX A: SUPPORTING INFORMATION FOR “PROGRESS TOWARDS DEVELOPMENT OF SOLID-SUPPORTED ACRIDINIUM PHOTOCATALYSTS ...... 67 A.1 General Reagents ...... 67 A.2 Photostability Measurements ...... 67 A.3 Fluorescence Measurements ...... 72 A.4 Stern-Volmer Quenching Measurements ...... 77 A.5 Photophysics of anchored catalyst with applied electrochemical potential ...... 80

A.6 Catalyst Synthesis ...... 81 A.6.1 Synthesis of Catalyst 6 ...... 81 A.6.2 Synthesis of Acridinium 8...... 84 A.6.3 Synthesis of Acridinium 19...... 88 A.6.4 Synthesis of Acridinium 22...... 91 A.6.5 Synthesis of Acridinium 23...... 94 A.6.6 Synthesis of Acridinium 24...... 96 A.6.7 Synthesis of Acridinium 25...... 99 A.6.8 Synthesis of Acridinium A1...... 100 A.7 Reactions with the surface-anchored catalysts ...... 103 A.7.1 General reaction details...... 103 A.7.2 Specific reactions ...... 103 A.8 Recycling attempts with surface-anchored catalysts...... 106 APPENDIX B: SUPPORTING INFORMATION FOR “OXIDATION OF ALKYL BENZENES BY A FLAVIN PHOTOOXIDATION CATALYST ON NANO- STRUCTURED METAL-OXIDE FILMS ...... 108 B.1. SI Methods ...... 108 B.1.1. Materials ...... 108 B.1.2. Preparation of FTO|Oxide-FMN ...... 108 B.1.3. Experimental Setup ...... 109 B.1.4. Preparation of Fe(TPA) Complex ...... 109 B.1.5. UV-Vis Spectra ...... 110 APPENDIX C: SUPPORTING INFORMATION FOR “STRONGER THAN LITHIUM: PHOTOEXCITED ACRIDYL RADICAL AS A SUPER-REDUCTANT FOR SINGLE ELECTRON REDOX CHEMISTRY ...... 115 C.1 General Methods ...... 115 C.2 Electron Paramagnetic Resonance (EPR) measurements ...... 116 C.3 Electrochemical measurements ...... 117 C.4 Generation of 1 by photoreaction of 2 and DIPEA ...... 120 C.5 Example reaction setup ...... 120

C.6 Fluorescence experiments ...... 121 C.7 Determination of excited state oxidation potentials ...... 124 C.8 Catalyst Preparation ...... 125 C.9 Substrate Synthesis ...... 127 C.10 Generation of Acridine anion (7) and 9,10-dihydroacridine (6) ...... 131 C.11 Spectroelectrochemistry ...... 135 C.12 Mechanistic experiments ...... 137 C.13 Reductive dehalogenation of alkyl halides...... 138 REFERENCES ...... 139

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LIST OF FIGURES

Figure 1.1: A simplified description of photophysical processes upon photon absorption ...... 4

Figure 1.2: Structures of common flavins in nature ...... 11

Figure 2.1: (A) Absorption spectrum of 6a on various metal oxides, (B) Absorbance at 425nm of 6a-Al2O3 in dichloromethane solution over time with no irradiation ...... 19

Figure 2.2: (A) Absorbance changes of 6a-Al2O3 during irradiation, (B) Absorbance changes during irradiation of 8-TiO2 ...... 23

Figure 2.3: (A) Spectral changes of 6a-Al2O3 during irradiation, (B) Spectra of 9-Mes-10-PhAcr BF4 with tBAOH before and after irradiation ...... 24

Figure 2.4: (A) Fluorescence decay of 6a in solution and on TiO2, (B) Stern-Volmer quenching of 6a-TiO2 with 16 ...... 29

Figure 2.5: Fluorescence decay traces (at 515nm) for catalysts 22 and 23 compared to solution phase decay of 6a ...... 31

Figure 2.6: Fluorescence lifetime of 6b-TiO2 as a function of applied potential ...... 33

Figure 2.7: Fluorescence lifetime decay traces (at 515nm) for carboxylate anchored catalysts on ZrO2 and comparison to siloxane anchored catalyst ...... 34

Figure 3.1: Structure of FMN and the surface-bound FMN assembly ...... 38

Figure 3.2: Spectral changes with time of FTO|ZrO2|-FMN films either stabilized with ALD or unstabilized...... 43

Figure 4.1: (A) Absorption spectra of acridinium 2 and acridyl radical 1. (B) Excitation wavelength dependent emission spectra of 1 ...... 51

Figure 4.2: (A) Spectral deconvolution of the excited state emission of 1 upon excitation at 385nm. (B) Normalized absorption, emission, and excitation spectra of 1 ...... 52

Figure 4.3: (A) Excitation wavelength dependent emission of 3. (B) Excitation spectra of 3 collected at varying emission wavelengths ...... 53

Figure 4.4: Plausible Jablonski depiction of the photophysical processes of 1 and 3 ...... 54

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Figure 4.5: Structures of 9,10-dihydroacridine 6 and acridine anion 7 ...... 60

Figure 4.6: Proposed mechanism for reductive dehalogenation of aryl halides ...... 61

Figure A.1: Initial photostability measurements of 6a-TiO2 ...... 68

Figure A.2: Selected spectra for initial photostability measurements of 6a-Al2O3 ...... 68

Figure A.3: Photostability measurements of 6a-ZrO2 ...... 69

Figure A.4: Photostability measurements of 6a-TiO2 ...... 69

Figure A.5: Photostability of 6a-Al2O3 in the presence of 0.01mmol 16 ...... 70

Figure A.6: Selected spectra from photostability measurements of 8-ZrO2 ...... 70

Figure A.7: Selected spectra for photostability measurements of 6b-Al2O3 ...... 71

Figure A.8: Spectral changes upon irradiation of 9-Mes-10-PhAcr BF4 with tBAOH ...... 71

Figure A.9: Selected spectra for photostability measurements of 19-TiO2 ...... 72

Figure A.10: Emission spectrum of 6a (16µM) in deoxygenated DCM ...... 73

Figure A.11: Normalized absorption and emission of 6a-TiO2 ...... 73

Figure A.12: Normalized absorption and emission of 6a-ZrO2 ...... 74

Figure A.13: Normalized emission of 6b-ZrO2 ...... 74

Figure A.14: Normalized absorption and emission of 12 in DCM ...... 75

Figure A.15: Lifetime decay traces for 6a in solution and at various loading times on TiO2 ...... 75

Figure A.16: Lifetime decay traces at 515nm for various surface anchored catalysts ...... 76

Figure A.17: Steady-state fluorescence spectrum of A1-TiO2 ...... 76

Figure A.18: Lifetime decay trace at 515nm for A1-TiO2 ...... 77

Figure A.19: Fluorescence lifetime of 6a (16µM) in deoxygenated DCM at the concentrations of 13 given ...... 78

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Figure A.20: Stern-Volmer quenching analysis of the lifetime data reported in Figure A.18 .....78

Figure A.21: Fluorescence lifetime of 6a-TiO2 in deoxygenated DCM at the concentrations of 13 given ...... 79

Figure A.22: Stern-Volmer quenching analysis of the lifetime data reported in Figure A.20 .....79

Figure A.23: Fluorescence lifetime of 6a-TiO2 (low loading time) in deoxygenated DCM at the concentrations of 16 given ...... 80

Figure A.24: Fluorescence lifetime of 6b-TiO2 at each applied potential ...... 81

Figure A.25: Normalized absorption and emission of 19-TiO2 ...... 90

Figure A.26: Absorption spectrum of 22-TiO2 ...... 94

Figure A.27: GCMS conversion trace for rearrangement of 16 catalyzed by 6a-TiO2 ...... 104

Figure A.28: Conversion of 16 by 6a-TiO2 after 60 minute cycles of irradiation ...... 106

Figure A.29: Conversion of 16 by 6b-TiO2 after 60 minute cycles of irradiation ...... 107

−11 −2 Figure B.1. UV-vis of a fully loaded (Γ = 5.7 × 10 mol cm ) FTO|ZrO2-FMN in oxygen-saturated MeCN/H2O (1/1 vol/vol) at room temperature ...... 110

Figure B.2. UV-vis of FTO|ZrO2-FMN, interval of 5 min in oxygen-saturated (A) MeCN/H2O (1/1 vol/vol) and (B) in DCE...... 111

Figure B.3. Plots of product conversion percent vs. reaction time for (A) ethylbenzene to acetophenone and (B) stilbene to benzaldehyde with FTO|ZrO2-FMN ...... 112

Figure B.4. NMR spectra showing the appearance of benzaldehyde upon oxidation of stilbene in the presence of FTO|ZrO2-FMN ...... 113

Figure B.5. NMR spectra showing the appearance of acetophenone upon oxidation of ethylbenzene in the presence of FTO|ZrO2-FMN ...... 113

Figure C.1: EPR spectrum of 1 ...... 117

Figure C.2: Cyclic voltammogram of 2 in acetonitrile ...... 117

Figure C.3: CV of 2 in acetonitrile showing the redox wave for reduction of 1 to 7 ...... 118

Figure C.4: Scan rate dependence of the various redox events in cyclic voltammetry of 2 ...... 118

Figure C.5: Evaluation of non-Nernstian behavior as a function of scan rate in the CV of 2 ....119

Figure C.6: Cyclic voltammogram of 4-chlorobenzonitrile in acetonitrile ...... 119

Figure C.7: Absorption spectra of 2 with DIPEA before and after irradiation ...... 120

Figure C.8: Normalized absorption, emission, and excitation spectra of 1 in hexanes ...... 122

Figure C.9: Excitation spectra of 1 collected by monitoring at different emission wavelengths...... 122

Figure C.10: Spectral deconvolution of the emission of 1 generated upon 385nm excitation ...123

Figure C.11: Normalized absorption and emission spectra for acridyl radical 3 ...... 123

Figure C.12: (A) Emission spectra collected at varying excitation wavelength for 3, (B) Emission intensity as a function of excitation wavelength at 579nm and 704nm ...... 124

Figure C.13: Excitation spectra of 3 in hexanes monitored at varying emission wavelength ....124

Figure C.14: Absorption spectrum of 7 in THF...... 132

Figure C.15: Spectroelectrochemical measurements of 2 in acetonitrile ...... 136

Figure C.16: Spectroelectrochemical measurements of 2 from -1900mV to -700mV ...... 137

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LIST OF SCHEMES

Scheme 1.1: Structural evolution of the acridinium class of photocatalysts ...... 10

Scheme 1.2: Progression of flavin catalyzed benzylic oxidations ...... 13

Scheme 2.1: Synthetic pathways to acridinium photocatalysts...... 17

Scheme 2.2: Synthesis of acridiniums bearing a siloxane anchoring group ...... 18

Scheme 2.3: (A) Proposed dealkylation to generate 9-mesitylacridine, (B) Absorbance spectra of 9-mesitylacridine and the solution following irradiation of 6a-Al2O3 ...... 20

Scheme 2.4: Synthesis of N-aryl acridinium 8 bearing a siloxane anchoring group ...... 22

Scheme 2.5: Anti-Markovnikov hydrocarboxylation attempts with free and anchored catalyst ..25

Scheme 2.6: Acridinium-catalyzed photomediated Newman-Kwart (NK) rearrangement ...... 26

Scheme 2.7: Newman-Kwart rearrangement catalyzed by surface anchored acridinium ...... 26

Scheme 2.8: Limited catalytic activity of surface anchored acridinium ...... 27

Scheme 2.9: Synthesis of catalyst 19 bearing a long alkyl tether ...... 29

Scheme 3.1: Generalized mechanism for the photooxidation of benzyl alcohol as a representative substrate by an FTO|ZrO2-FMN surface in the presence of O2 ...... 40

Scheme 4.1: Reductive dehalogenation of poly-halogenated anisoles ...... 59

Scheme 4.2: Reductive dehalogenation and intramolecular cyclization of 8 ...... 62

Scheme A.1: Synthetic pathway to catalyst 6 ...... 81

Scheme A.2: Synthesis of catalyst 8 ...... 84

Scheme A.3: Synthesis of catalyst 19 ...... 88

Scheme A.4: Synthesis of catalyst 22 ...... 91

Scheme A.5: Synthesis of catalyst 23 ...... 94

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Scheme A.6: Synthesis of catalyst 24 ...... 96

Scheme A.7: Synthesis of catalyst 25 ...... 99

Scheme A.8: Synthesis of catalyst A1 ...... 100

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LIST OF CHARTS

Chart 1.1: Representative Electrochemical Scale...... 5

Chart 4.1: Substrate Scope of Reductive Dehalogenation Catalyzed by Acridinium 2 ...... 57

Chart 4.2: Initial extension of the reductive deoxygenation substrate scope ...... 64

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LIST OF TABLES

Table 3.1. Control experiments with benzyl alcohol to benzaldehyde as the model reaction ...... 44

Table 3.2. Substrate scope for photooxidation by FTO|ZrO2|-FMN ...... 45

Table 4.1: Initial optimization of reductive dehalogenation ...... 55

Table 4.2: Wavelength dependent reactivity of substrates of varying reduction potential ...... 56

Table 4.3: Optimization of the protecting group for reductive deoxygenation of 9a ...... 64

Table B.1. Substrates scope for photooxidation by FTO|ZrO2-FMN with [Fe(TPA)(MeCN)2](ClO4)2 cocatalyst ...... 114

LIST OF ABBREVIATIONS

∆E Change in electrochemical potential

μs Microsecond

13C NMR Carbon-13 nuclear magnetic resonance

1H NMR Proton magnetic resonance

9-MesNMA 9-mesityl-N-methylacridinium

Al2O3 Aluminum oxide

ALD Atomic layer deposition

BDE Bond dissociation energy

BET Back electron transfer cat catalyst

CB Conduction Band

CT Charge transfer

D1 Lowest electronic energy doublet excited state

DCE 1,2-Dichloroethane

DCM Dichloromethane

DFT Density functional theory

DIPEA N,N-diisopropylethylamine

DSPEC Dye-sensitized photoelectrosynthesis cell

DSSC Dye-sensitized solar cell e− Electron

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E∗ Excited state redox potential

E0,0 Excited state energy

E1/2 Half-wave potential

Ep/2 Half-peak potential

EnT Energy transfer

EPR Electron paramagnetic resonance

ET Electron transfer

ℱ Faraday constant

FAD Flavin adenine dinucleotide

FMN Flavin mononucleotide

FTO Fluorine-doped tin oxide

G Symbol for Gibb’s free energy

GCMS Gas chromatography–mass spectrometry

H2O2 Hydrogen peroxide

HMDSO Hexamethyldisiloxane

IC Internal conversion

IR Infrared spectroscopy

ISC Intersystem crossing k General symbol for rate constant

LE Locally excited state

LED Light-emitting diode

MBA 4-methoxybenzylalcohol

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MeCN Acetonitrile

NAD Nicotinamide adenine dinucleotide

NK Newman-Kwart rearrangement

NMA N-methylacridinium

−• O2 Superoxide

PCET Proton-coupled electron transfer

PET Photoinduced electron transfer

PMMA Poly(methyl methacrylate)

RFTA Riboflavin tetraacetate

S1 Lowest electronic energy singlet excited state

SCE Saturated calomel electrode

SDS Sodium dodecyl sulfate

SET Single electron transfer sub substrate

T1 Lowest electronic energy triplet excited state

TD-DFT Time dependent density functional theory

TICT Twisted intramolecular charge transfer

TiO2 Titanium dioxide

UV-vis Ultraviolet-visible absorption spectroscopy

VB Valence Band

VR Vibrational relaxation

ZrO2 Zirconium dioxide

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CHAPTER 1: INTRODUCTION TO ACRIDINIUM AND FLAVIN VISIBLE LIGHT PHOTOREDOX CATALYSIS

1.1 Introduction

The conversion of light into chemical energy for the manipulation of molecular structure has been known and extensively studied over the past century.1 However, it is only in the past decade that the field of photochemistry has witnessed broad synthetic utility in the development of new bond constructions.2–4 This is attributed primarily to the development of sensitized photocatalysis, particularly with the use of visible light excitation. A rapidly expanding number of new reaction methodologies have been developed, taking advantage of energy transfer (EnT) and single electron transfer (SET) pathways mediated by simple organic dyes or organometallic complexes. In particular, the latter pathway has received much attention due to the generation of highly reactive open-shell intermediates. Borrowing from the electrochemical description of electron transfer as oxidation and reduction events, the term “photoredox catalysis” has been coined to describe this area. In addition to new reaction development, enabled by mechanistic pathways made possible only through open-shell intermediates, the field of photoredox catalysis is characterized by operationally mild conditions.

Nevertheless, despite the wealth of new chemical reactivity made accessible by photoinduced electron transfer, the commercial applicability of these reactions is still quite limited. This may be attributed in part to the expense of the organic or organometallic photocatalyst which may frequently cost as much as $1000-$2000/g.5,6 Catalyst recovery and

1 recycling is also not broadly established.7 An additional limitation in the field of photoredox catalysis is simply the few number of well-studied catalytic systems. Extensive spectroscopic and electrochemical work throughout the 20th century laid the groundwork for understanding the photophysical behavior of excited state chromophores. However, catalyst development may at best still be described as only in its early adolescence, with the majority of reports still focused on the use of iridium and ruthenium photosensitizers. Significant progress has been made in the development of robust organic photocatalysts, but, as we will demonstrate later, the mechanisms and photophysics of many of these systems are still being explored.2

The goals of the research disclosed here are to specifically address, in part, the limitations described above. Efforts towards catalyst recycling and reduction of cost are a major focus.

Additionally, investigations into the photophysics and reactivity of acridinium chromophores has contributed to further development of this class of organic photoredox catalysts. Nevertheless, before detailed description of this work, it is necessary first to discuss the fundamental principles of photoredox catalysis. This chapter will also describe the development of acridinium and flavin photoredox catalysts.

1.2 Fundamental principles of photoredox catalysis

1.2.1 Photophysical processes

A comprehensive review of the photophysical processes involved upon light absorption has been provided elsewhere.8 What follows is an abbreviated and generalized description of the processes considered to be most relevant.i

It is first assumed that the wavelength(s) of irradiation for a desired photoredox reaction must overlap with the absorption spectrum of the catalyst. For the controlled generation of

i Rare processes such as direct singlet to triplet (S0→T1) absorption or emission from higher excited states (>S1) are ignored here.

2 reactive intermediates, it is likewise imperative that no other species in the reaction possess significant absorption at the selected wavelength(s). For these reasons, to avoid direct substrate excitation, the use of visible light is generally preferable.

Providing the catalyst is a closed shell species, absorption of a photon results in promotion to a singlet excited state (Figure 1.1). Although excitation to the lowest vibrational and electronic singlet excited state is possible, frequently higher energy electronic and vibrational levels are populated. However, rapid internal conversion and vibrational relaxation quickly result in population only of the lowest energy singlet excited state, S1. Decay to the ground state often occurs on the nanosecond time scale and may be accomplished by emission of fluorescence (kr) and non-radiative relaxation (knr). If the rate of intersystem crossing (kISC) is fast enough to compete with these relaxation modes, then the lowest energy triplet state, T1, may also be populated. Decay of the triplet state typically occurs on a much longer time scale (e.g. microseconds) than fluorescence since the T1→S0 transition is spin forbidden. Single electron transfer processes relevant to photoredox catalysis may therefore occur from either the S1 or T1 excited states and will depend on the energies and relative populations of each state.

1.2.2 Thermodynamics of Photoinduced Electron Transfer (PET)

The thermodynamic driving force for an electron transfer event is dependent on the electrochemical redox potentials of the species involved.2 This may be described by the following equation

−• +• ∆GPET = −nℱ∆E = −nℱ[Ered(A/A ) − Eox(D /D)] where n is the number of electrons transferred, ℱ is Faraday’s constant (23.061 kcal V-1 mol-1),

Figure 1.1: A simplified description of photophysical processes upon photon absorption.

ii Ered is the reduction potential of some electron acceptor, A, and Eox is the oxidation potential of some electron donor, D. In photoredox chemistry, single electron transfer processes are by far the most common (i.e. n = 1). For photoinduced electron transfer, there are two possible scenarios. If the catalyst acts as an oxidant (i.e. is itself reduced), then the Gibb’s free energy for electron transfer may be expressed as follows

∗ ∗ −• +• ∆GPET = −ℱ[퐸푟푒푑(cat /cat ) − Eox(sub /sub)]

∗ where 퐸푟푒푑 is the reduction potential of the excited state to which electron transfer occurs.

∗ Because of the short intrinsic lifetime of excited states, 퐸푟푒푑 is not directly measured but is instead estimated from the ground state redox potential, 퐸푟푒푑, and the electronic energy of the

iii excited state of interest, 퐸0,0 :

∗ 퐸푟푒푑 = 퐸푟푒푑 + 퐸0,0

In the event that the photoredox catalyst acts as an excited state reductant, the Gibb’s free energy

ii The term “oxidation potential” is often a cause of confusion, particularly as it is written as a reduction half reaction. See reference 2 for a more detailed description. iii Because of the rapid relaxation to the lowest energy excited state described above, this value is typically labeled as E0,0. Some caution in the use of this moniker should be exercised since reaction from higher excited states has been reported (see Chapter 4). Nevertheless, as a general example we shall continue to use it here.

Chart 1.1: Representative Electrochemical Scale

for electron transfer is expressed as follows

−• ∗ +• ∗ ∆GPET = −ℱ[Ered(sub/sub ) − 퐸표푥(cat /cat )]

∗ where 퐸표푥 is the oxidation potential of the excited state from which electron transfer occurs and

∗ may be estimated similarly to 퐸푟푒푑:

∗ 퐸표푥 = 퐸표푥 – 퐸0,0

∗ From these equations, it may be seen that 퐸푟푒푑 is reported as a positive value for

∗ photooxidants while 퐸표푥 is reported as a negative value for photoreductants. Additionally, for

∗ photoinduced electron transfer to be thermodynamically favorable in these cases, 퐸푟푒푑 must lie at

∗ a more positive value than the ground state oxidation potential of the substrate and 퐸표푥 must lie at a more negative potential than the ground state reduction potential of the substrate. Given these requirements, the construction of electrochemical scales is often helpful in illustrating the relative redox window of a particular catalyst. Chart 1.1 provides a representative example.

2+ As can be seen from the chart, Ru(bpz)3 is a strong enough excited state oxidant to undergo single electron transfer with trans-anethole or the pyrrolidine enamine of cyclo- hexanone. However, it is not a strong enough oxidant to remove an electron from 3-chloro-훽-

3+ methyl styrene. Likewise, on the reducing side, Ir(ppy)3 in its excited state is reducing enough to undergo electron transfer with 2-bromoacetophenone or diethyl 2-bromomalonate. However, aryl halides with more negative reduction potentials are outside the range of this catalyst.

1.2.3 Example reactions

A host of new reaction methodologies have been developed making use of the oxidizing and reducing power of catalyst excited states.2–4 As many of these transformations have been the subject of several excellent reviews articles, we will only mention two examples here for illustration. The first example makes use of the enhanced oxidizing capability of the catalyst excited state. An Aza-Henry reaction with tertiary amines via oxidative C–H functionalized was demonstrated in 2010 by Stephenson and coworkers.9 Upon visible light excitation, the iridium catalyst is promoted to its excited state. Single electron oxidation of the tertiary amine generates an amine cation radical and a reduced iridium intermediate. This intermediate is a strong ground state reductant and will reduce oxygen or nitromethane to the radical anion, turning over the photocatalyst. The radical anion generated is proposed to abstract a hydrogen atom from the benzylic position of the tertiary amine, resulting in the formation of an iminium ion which is then trapped by nucleophilic addition to yield the final product.

An excellent example of single electron reduction occurring from a catalyst excited state is the direct trifluoromethylation of arenes reported by MacMillan and coworkers in 2011.10

Here, visible light excitation of a ruthenium phenanthroline catalyst generates a moderately

2+ reducing excited state. Single electron transfer from the excited Ru(phen)3 to trifluoro- methanesulfonyl chloride results in the generation of a trifluoromethyl radical. This highly electron deficient radical is then captured by the most electron rich position of the arene. The

3+ resulting cyclohexadienyl radical is then oxidized by Ru(phen)3 to turn over the catalyst, and subsequent deprotonation generates the final C–H-functionalized product.

1.3 Development of Acridinium and Flavin Photoredox Catalysts

1.3.1 Evolution of Acridinium Photoredox Catalysis

The acridinium class of catalysts is among the most heavily studied organic photoredox systems.2 Their absorption spectra lie generally in the blue region of the visible spectrum and they often possess extremely high excited state reduction potentials. As a result, a host of new reaction methodologies have been developed taking advantage of the potent oxidizing power of these catalysts. However, as many of these transformations have been reviewed elsewhere, we will focus only on the structural development of this class of photoredox catalysts.

N-Methyl acridinium (NMA) is perhaps most representative of the advantages and challenges associated with the acridinium class. NMA is a potent oxidant in its singlet excited

∗ 11 state with 퐸푟푒푑 = +2.32 V vs. SCE. Additionally, NMA possesses an extremely long singlet lifetime of 31ns and a fluorescence quantum yield of unity.12,13 Nevertheless, although these features make NMA highly attractive as a photocatalyst, it has received relatively little application owing to its high susceptibility to nucleophilic and radical deactivation at the 9- position.14,15 Indeed, observation of these modes of deactivation, at positions not limited to the 9- position, has been a driving force for multiple iterations of structural modification to the acridinium core.

Phenyl substitution at the 9-position showed a decrease in radical deactivation.15

However, the excited state lifetime of 9-PhNMA is significantly reduced due to rotational freedom of the phenyl ring, and susceptibility to nucleophilic addition was still observed.16,17 The introduction of 9-mesityl-N-methyl acridinium (9-MesNMA) by Fukuzumi in 2004 brought a significant improvement in the catalytic properties of acridiniums.18 The bulky mesityl group

8 served to effectively block radical and nucleophilic addition at the 9-position, and many transformations have been reported with this catalyst.2

The photophysics of 9-MesNMA were initially the subject of contentious debate where reactivity was originally described as resulting from a long-lived charge separated state.13,19–22

However, after thorough investigation, a thermal equilibrium of locally excited singlet (1LE) and intramolecular charge transfer singlet (1CT) states was identified upon visible light excitation.23

Although, photoinduced electron transfer may occur to either state, it has been demonstrated that the 1CT state is not necessary for PET to occur and may in fact serve as a pathway for catalyst deactivation (vide infra).

Although 9-MesNMA has seen wide employment in photoredox catalysis, catalyst deactivation by nucleophilic demethylation at nitrogen has been reported in several cases.24–26

Furthermore, dearomatization caused by nucleophilic and possibly radical addition has also been observed, suggesting that the 9-position is not the only one susceptible to addition.25

Replacement of the N-methyl group with a phenyl substituent has led to significantly increased stability. Methyl substitution at the 2- and 7- positions was also found to be beneficial.25

However, the most robust acridinium thus far developed has featured tert-butyl substitution at the 3- and 6-positions.27,28 These bulky substituents, in conjunction with the 9-mesityl, are proposed to block nucleophilic and radical addition to the acridinium core.

Despite the multiple structural optimizations described above, catalyst degradation remains common in many photoredox reactions. Nucleophilic addition to the excited state acridinium has been proposed.28 Also, benzylic oxidation of the mesityl group has been commonly observed.28,29 The mechanism of this functionalization is proposed to occur through the 1CT state described above. As a result, acridinium catalysts bearing less electron rich groups

9 at this position have recently been developed.30 Further investigation of catalyst deactivation is clearly needed and is only possible through continued examination of the excited state properties of this class of photocatalysts.

Additionally, modulation of the electronic properties should also be investigated. The vast majority of acridinium photocatalysts reported possess excited state reduction potentials between +2.00 V and +2.20 V vs. SCE.30 The use of a less oxidizing catalyst has been shown in some cases to have a significant effect on catalysis.26 Therefore, further analysis of catalyst electronics should be attempted.

In conclusion, the structural evolution of acridinium photooxidants has been described.

From this, it may be seen that the development of this class of photocatalysts is still young and very much in progress. Significant improvements in catalyst stability, and hence reactivity, have been achieved. However, it is clear that continued photophysical investigations are necessary and we are confident that these will lead to a deeper understanding of optimal catalyst design.

Scheme 1.1: Structural evolution of the acridinium class of photocatalysts.

1.3.2 The Development of Synthetic Flavin Photoredox Catalysis

Flavin photocatalysis has been extensively studied over the past century, primarily in biochemical settings.31–33 The term “flavin” itself comes from the bright yellow color of the isoalloxazine unit common to these structures. In nature, flavins exist most commonly as flavin

Figure 1.2: Structures of common flavins in nature. mononucleotide (FMN) and flavin adenine dinucleotide (FAD), and a host of flavoproteins containing these cofactors have been reported. Nevertheless, for applications in synthetic photocatalysis, free flavins such as riboflavin (Vitamin B2) have received the greatest amount of attention. As the ribityl side chain of riboflavin is sensitive to oxidative degradation, the use of riboflavin tetraacetate (RFTA) is far more common in photoredox literature. Additionally, since the mid-1980s, the photooxidation of substituted benzyl alcohol derivatives has been the most widely studied synthetic application of flavin photocatalysts. For this introduction, we will discuss the development of these reactions with a focus on the progression of catalytic systems involving RFTA and its derivatives.

34 ∗ RFTA absorbs maximally near 440nm in the blue region of the visible spectrum. 퐸푟푒푑 of RFTA is moderately oxidizing and lies around +1.8 V vs. SCEiv making it an excellent photocatalyst for study.34 In the late 1980s, Fukuzumi noted that no appreciable oxidation of benzyl alcohol was observed under irradiation of RFTA in acetonitrile.35 However, addition of acid to form RFTA-H+ resulted in a shift to higher oxidizing potentials and efficient conversion of benzyl alcohols with oxidation potentials around +1.9 V vs. SCE could be achieved.

Nevertheless, benzyl alcohols with highly electron withdrawing substituents could not be accessed in this manner.

Fukuzumi followed this report with a detailed investigation of the effect of metal ion

Lewis acids on flavin catalysis.36 Coordination to one or both carbonyl groups of RFTA resulted in a shift, sometimes significant, of the excited state reduction potential to more positive values.

In particular, the addition of scandium triflate caused an increase of 780mV in the reduction potential of the singlet excited state, and oxidation of toluene could now be achieved.

However, as the use of rare earth metal ions is non-ideal, continued efforts were made to improve the RFTA catalytic system. In the absence of Lewis acids, improved efficiency for benzyl alcohol oxidation was reported with the use of SDS micelles in acetonitrile solution.37

The presence of a thiourea additive was also found to cause a significant increase in the quantum yield of reaction.38 However, the use of aqueous solvent or water acetonitrile mixtures was found to have the greatest effect on catalysis.31,39,40 Substrates previously inaccessible without the addition of Bronsted or Lewis acid could now be oxidized in moderate to good yields. The importance of water to this reaction has been attributed to an enhanced rate of protonation

iv This value is highly solvent dependent. Additionally, protonation of the flavin can also significantly impact this value.

Scheme 1.2: Progression of flavin catalyzed benzylic oxidations. following electron transfer (vide infra) and to the extended lifetime of the triplet excited state in this solvent.31

A detailed mechanistic investigation of the photooxidation of 4-methoxybenzyl alcohol

(MBA) using transient absorption was conducted by Riedle and coworkers.41 Upon photoexcitation to the 1RFTA state, they determined that electron transfer to this state resulted in no productive chemistry as back electron transfer (BET) was extremely rapid. Instead, after intersystem crossing to 3RFTA, productive single electron oxidation of MBA generated the

RFTA radical anion and the substrate radical cation. Back electron transfer is spin forbidden and therefore slow, allowing time for proton transfer to produce a neutral flavin radical and the MBA benzylic radical. Further oxidation of the benzylic radical in the presence of molecular oxygen generates the final product.

Having identified 3RFTA as the excited state responsible for productive oxidation, several attempts to increase the efficiency of intersystem crossing have been made.31,42,43 Heavy atom substitution on the isoalloxazine core has in some cases been shown to result in improved yields of photooxidation. Other structural modifications have also been reported.44

Immobilization of flavins on solid supports for heterogeneous photoredox catalysis has also been reported.39 König and coworkers prepared flavins anchored onto silica gel and entrapped in polyethylene pellets. Although moderate recycling for benzylic oxidations could be achieved, catalyst turnover numbers and overall efficiencies were significantly lower than those reported for RFTA in solution.

In conclusion, the development of flavins in synthetic photoredox catalysis has been briefly described. Modification of the flavin excited state redox potentials could be achieved through the use of Brønsted or Lewis acids. The presence of water has also been found to have a beneficial effect on catalysis. Limited success has been achieved with the use of immobilized flavins in photoredox catalysis and we believe that this area might benefit from further study.

1.4 Conclusions

Photoredox catalysis is a highly interesting field of study and one that has generated significant attention in recent years. A diverse array of new chemical methodology has been developed by taking advantage of single electron transfer pathways mediated by simple organic and organometallic chromophores. However, the field is still quite young and many catalytic systems remain in early development. The photocatalyst classes described above serve as examples both of the progress that has been made in recent decades and of the need for further study. Our efforts in the areas of acridinium and flavin photocatalyst development are described herein.

CHAPTER 2: PROGRESS TOWARDS DEVELOPMENT OF SOLID-SUPPORTED ACRIDINIUM PHOTOCATALYSTS

2.1 Introduction

The area of photoredox catalysis has grown tremendously over the past decade, due primarily to the wealth of new chemical reactivity that has become accessible under this manifold. This growth has been propelled by the development and application of a host of organic and organometallic chromophores (i.e. photoredox catalysts) with varying excited state properties.2,3 Photoinduced energy transfer (ET), single electron transfer (SET), and proton coupled electron transfer (PCET) pathways have emerged as common terminology. However, the commercial economic viability of many of these new transformations is limited by the cost of the photocatalyst, which can easily range as high as $1000-$2000 per gram.5,6 This prohibitive cost creates the desire to use extremely low catalyst loadings and recycle the catalyst.

One potential solution to these challenges comes from the field of supported homogeneous catalysis.45,46 This approach involves the modification of traditional solution phase catalysts so that they may be anchored onto a solid surface such as silica, a metal oxide, or a polymeric support. The advantages of this approach can be quite significant: the catalyst retains a well-defined and modular active site while gaining ease of separation and, in some cases, increased stability. While this approach has been successfully demonstrated numerous times for non-photochemical processes, application in the field of photoredox chemistry has up to this point remained very limited.47–49

Thin-film, nanoporous metal oxides have been used extensively in dye-sensitized solar cells (DSSCs) and dye-sensitized photoelectrochemical cells (DSPECs).50–53 Their high internal to geometric surface area ratios, generally 200-1000, render them attractive supports for light harvesting applications.54–56 However, although extensive use has been made of nanoporous metal oxides in aqueous CO2 reduction and water oxidation, extension of these materials as catalyst supports for organic photoredox chemistry has not been widely explored.

Acridinium dyes represent a class of highly oxidizing organic photoredox catalysts. Their visible light absorption (400-450nm) and high excited state reduction potentials (ca. +2.1 V vs.

SCE) have resulted in wide usage in the development of new single electron pathways.2 Here we report our progress in the development of metal oxide supported acridinium photoredox catalysts with the goal of recyclable catalysis.

2.2 Results and Discussion

2.2.1 Synthetic Efforts towards Acridiniums Functionalized with a Siloxane Anchoring Group

Although several synthetic approaches have been reported for the preparation of acridinium salts, only two methods are heavily used in the literature (Scheme 2.1).13,26,27,57

Method A involves the quaternization of 9-substituted acridine with a strong alkylating agent such as methyl iodide. This approach is very reliable, but substitution at the 10-position is limited to activated alkyl electrophiles such as methyl iodide. However, dealkylation of the 10- position during photochemical reactions is a common problem encountered in several reports.24–

26 Method B, on the other hand, is amenable to aryl substitution at the 10-position. Beginning with an acridone, simple alkylation or aryl coupling is used to install substitution at the 10-

Scheme 2.1: Synthetic pathways to acridinium photocatalysts position followed by Grignard or organolithium addition to install substitution at the 9-position.

The 9-position is known to be highly susceptible to nucleophilic addition and so a bulky group

(e.g. mesityl) is usually installed at this position.2 At the beginning of our investigations, we chose to craft our synthetic approach using method B due to the broader range of substitution made accessible by this route.

A variety of surface anchoring groups have been studied, primarily in the context of solar energy conversion.58–62 By far the most common surface anchoring groups reported are carboxylates and phosphonates. Although carboxylic acids are widely abundant and inexpensive, the use of harsh nucleophiles in Method B necessitates protection of the acid and later deprotection. The instability of phosphonates to harsh nucleophiles is likewise well documented.63–65 Siloxanes are an alternative anchoring group reported to provide high surface stabilities.66–69 Additionally, bulky siloxanes are reported to be compatible with harsh nucleophiles such as Grignard reagents,70,71 making them synthetically attractive as they can be carried intact through multiple steps prior to surface attachment. For these reasons, we chose to focus our attention on acridinium structures bearing a siloxane anchoring group.

It was reasoned that installation of the anchoring group could be achieved via a simple

Scheme 2.2: Synthesis of acridiniums bearing a siloxane anchoring group. alkene hydrosilylation with trichlorosilane. Condensation of the resulting trichlorosilane with surface hydroxyl groups on the metal oxide should result in a stable surface linkage. With this in mind, we set 1 as our initial target structure.

Allylation of acridone 2 proceeded smoothly to furnish 3 in good yield, and organolithium addition followed by acid precipitation in diethyl ether led to acridinium 4.

Unfortunately, upon hydrosilylation of 4 with trichlorosilane, we obtained only degradation products, possibly through silylation of the heteroaromatic core. Returning to 3, we altered our synthetic route to perform hydrosilylation prior to Grignard addition. This approach met with much greater success. Hydrosilylation proceeded cleanly and trapping with isopropanol furnished the bulky siloxane 5 in moderate yields. Treatment of 5 with mesityl magnesium bromide led to the corresponding acridinol which, after column chromatography and crystallization, afforded 6a.

2.2.2 Loading and “Dark” Stability

2 Surface loading of 6a on metal oxide thin films (4μm, 1cm TiO2, ZrO2, or Al2O3 on FTO glass, see Experimental section of Appendix A) was investigated. No significant surface

Figure 2.1: (A) Absorption spectrum of siloxane anchored catalysts 6a on various metal oxides, (B) Absorbance at 425nm of 6a-Al2O3 in dichloromethane solution over time with no irradiation. coverage was noted after soaking a ZrO2 slide in a methylene chloride solution of 6a for approximately 30 minutes. Hydrolysis of the bulky siloxane is likely slow in nonpolar solvent at room temperature. Literature on the related silatrane anchoring group reports good loading at slightly elevated temperatures in polar solvent.28 Heating an acetonitrile solution of 6a at 70 oC for 3 hours gave good surface coverage on all three metal oxide slides ranging from Γ = 2.7 –

-8 2 9.2 × 10 mol/cm (Figure 2.1A). The highest surface loadings were observed for TiO2 films.

The surface loading showed a dependence upon concentration of the loading solution, and so extended loading times (i.e. 12–24 hrs) in concentrated solutions were generally used to ensure higher surface coverage. Finally, to confirm surface stability in the absence of irradiation, we monitored the absorption spectrum of an Al2O3 slide loaded with 6a in dichloromethane (DCM) over a period of 12 hours and saw no appreciable change in absorbance at 425nm over this time period (Figure 2.1B).

Scheme 2.3: (A) Proposed dealkylation to generate 9-mesitylacridine, (B) Absorbance spectra of 9-mesitylacridine and the solution following irradiation of 6a-Al2O3 with a 3W 450nm LED in acetonitrile for several hours.

2.2.3 Initial Photostability Results

Having established the loading and dark stability of catalyst 6a on the surface, we next investigated the photostability of the surface-bound material. For ease and clarity the catalyst metal oxide assemblies are referred to as 6a-ZrO2, 6a-Al2O3, and 6a-TiO2. Irradiation of 6a-

TiO2 in acetonitrile with 450nm blue light led to a relatively rapid loss of absorbance

(approximately 25%) at 425nm during the first hour of irradiation. However, absorbance loss was not uniform across the spectrum, suggesting that catalyst degradation, rather than simply desorption, may be occurring. Indeed, after photostability measurements of 6a-Al2O3 in acetonitrile, the remaining solution gave evidence of the presence of 9-mesitylacridine (7). It is proposed that this acridine is formed by dealkylation of the anchored acridinium by some resident nucleophile (surface hydroxyls, etc.).

Dealkylation of 6a, if established, would pose a significant barrier to the utility of the surface-bound catalyst. To confirm our results, we examined the photostability of 6a-Al2O3 in

1,2-dichloroethane (DCE) as it is a more common solvent for photoredox reactions. In this

20 experiment, we observed broad and very rapid loss of absorbance (77% loss at 425nm after 9 minutes of irradiation) indicating significant desorption. UV-Vis of the remaining solution gave no clear indication of the presence of mesityl acridine.

2.2.4 Improved Photostability

The inconsistency in photostability measurements and the extremely low surface stability led us to examine the system in more detail. Based on the literature reports, the siloxane anchor was expected to be extremely stable under most normal reaction conditions72 and yet we observed degradation and clear loss of the catalyst from the surface. We reasoned that there could be two probable causes of the instability.

First, the N-alkyl bond is known to be susceptible to nucleophilic cleavage.24–26 It was not initially apparent what nucleophiles might be present in the system,v but this dealkylation pathway seemed possible given the previous indication of 7 in solution.

Alternatively, we reasoned that the siloxane anchoring group might be sensitive to oxygen in the system. Oxygen has previously been reported to cause significantly decreased surface stability in the case of carboxylate and phosphonate anchored ruthenium polypyridyl complexes, possibly through the generation of reactive oxygen species.73 Some acridiniums are known to act as singlet oxygen sensitizers, while the fully unsubstituted acridine is reported to generate singlet oxygen with high quantum efficiencies.74 Additionally, the acridyl radical resulting from reduction of 9-mesityl-10-methyl acridinium has been proposed to generate

−• 75 superoxide (O2 ). Thus, the presence of oxygen might be a cause of the observed surface instability.

Considering both potential causes of surface instability, we first examined the effect of

v The identity of the counterion as hydroxyl had not yet been determined (vide infra).

Scheme 2.4: Synthesis of N-aryl acridinium 8 bearing a siloxane anchoring group. oxygen on the system. Thoroughly sparging the system for 30 minutes with nitrogen prior to irradiation led to a dramatic increase in the photostability (Figure 2.2A). After 60 minutes of irradiation we saw greater than 75% retention of the surface absorption at 425nm for 6a-Al2O3 in

DCM. Repeating the experiment now resulted in high reproducibility. Photostability measurements on TiO2 and ZrO2 in rigorously deoxygenated conditions yielded slightly diminished but comparable results.

For comparison, we also examined the possibility of dealkylation. Acridinium 8, containing an aryl group at the 10-position, was synthesized (Scheme 2.4) and the subsequent photostability surveyed (Figure 2.2B). In this new material, the dealkylation pathway previously suggested to be problematic is no longer possible. Photostability measurements of 8-TiO2 in a system where oxygen was not excluded resulted in rapid desorption (i.e. complete loss of absorbance at 425nm in less than 20 minutes of irradiation). Alternatively, after removal of oxygen from the system, surface retention was largely improved with no significant desorption observed over 60 minutes of irradiation.vi From these results, it may be concluded that oxygen sensitivity is the primary cause of surface instability rather than nucleophilic cleavage.

vi Catalyst degradation on the surface, however, was observed.

Figure 2.2: (A) Absorbance changes near 427nm of 6a-Al2O3 in DCM or DCE solution during irradiation with 3W 450nm LED under the following conditions: not degassed thoroughly (red diamonds), degassed 30 minutes with nitrogen (blue triangles), and degassed 30 minutes with nitrogen (reproducibility check, blue squares). (B) Absorbance changes near 427nm during irradiation of 8-TiO2 in DCE solution with 3W 450nm LED under the following conditions: not degassed (green circles), degassed 30 minutes with nitrogen (purple cross squares).

2.2.5 Counterion Identity and Catalyst Degradation

Although surface stability was dramatically improved by the rigorous exclusion of oxygen, the overall catalyst stability was less than ideal. During photolysis, clear degradation of the acridinium on the surface was noted. Bleaching of the prominent acridinium band at 425nm accompanied by the growth of a new absorption at 385nm was observed (Figure 2.3A). The presence of a clear isosbestic point near 400nm suggests direct conversion of the acridinium to a single degradation species. Upon further investigation, it is believed that this degradation species is the result of an adduct that forms with hydroxide. After synthesis, catalysts 6a and 8 were purified by column chromatography. After crystallization, no subsequent ion exchange was performed out of concern of siloxane hydrolysis.vii Further characterization confirmed the

vii Siloxane hydrolysis is documented in the literature and in some cases hindered isolation of crystalline material. Even in solid form, very slow hydrolysis of the siloxane was observed.

Figure 2.3: (A) Spectral changes of 6a-Al2O3 in deoxygenated DCM upon irradiation with 3W 450nm LED. (B) Spectra of a deoxygenated DCM solution of 9-mesityl-10-phenylacridinium tetrafluoroborate (50µM) in the presence of tetrabutylammonium hydroxide (100µM, 2 equiv.) before (blue) and after (red) irradiation with 3W 450nm LED. identity of the counterion to be hydroxide. Irradiation of 8 in dichloromethane solution resulted in rapid decomposition to the degradation species previously observed on the metal oxide surface. Additionally, irradiation of 9-mesityl-10-phenyl acridinium tetrafluoroborate in the presence of tetrabutylammonium hydroxide resulted in the same degradation species. IR measurements also support the assignment of the counterion as hydroxide. Ion exchange with sodium perchlorate to generate 6b resulted in significantly enhanced surface stability. Only slow desorption of 6b-Al2O3, with no indication of degradation, was observed during photolysis (see

Appendix A).

Scheme 2.5: Anti-Markovnikov hydrocarboxylation attempts with free and anchored catalyst.

2.2.6 Catalytic Activity of Surface-Tethered Acridinium Catalysts

Having established solid-supported acridiniums with high surface stability, the catalytic behavior of these materials was evaluated in several test reactions.viii Anti-Markovnikov addition of carboxylic acids to styrenes via acridinium photocatalysis has previously been reported by our group.76 The addition of acetic acid to trans-anethole proceeded in full conversion under irradiation of 6a in solution (Scheme 2.5). However, no product formation was observed in the presence of 6a-ZrO2, even at long irradiation times. Modifying the system with an alternate hydrogen atom donor also showed no conversion. The solid support was completely bleached in both reactions.

The introduction of the solid support may pose a number of challenges, particularly for intermolecular reactions. Possible adsorption of substrate onto the solid surface may limit diffusion or increase the propensity for back electron transfer (BET). The requirement for base and a hydrogen atom donor may add additional complication to the system. The recently reported photoredox mediated Newman-Kwart rearrangement offers a simplified system for investigating initial reactivity of the surface-tethered catalysts.77 Noting the catalyst bleaching observed over long irradiation in the previous test systems, the Newman-Kwart rearrangement also offers the advantage of short reaction times at low substrate concentration.

viii Initial catalytic investigations were made prior to determination of the catalyst counterion identity.

Scheme 2.6: Acridinium-catalyzed photomediated Newman-Kwart (NK) rearrangement.

Scheme 2.7: Newman-Kwart rearrangement catalyzed by surface anchored acridinium.

Although the Newman-Kwart rearrangement was reported in acetonitrile using a pyrylium photocatalyst, 9-mesityl-10-methylacridinium (12) showed efficient conversion of several substrates (13-15) in dichloromethane solution after only 60 minutes irradiation time

(Scheme 2.6). Using the surface-bound catalyst 6a-TiO2, we were gratified to see full conversion of the isoeugenol-derived thiocarbamate (16) in equivalent irradiation time. High conversion with 6a-ZrO2 and 6a-Al2O3 was also observed. Since the highest catalyst surface coverage and the best reaction conversion were observed with 6a-TiO2, we selected this metal oxide catalyst assembly for further investigations.

Catalyst recycling is a major goal of these investigations. However, attempts to recycle the catalyst in this transformation were largely unsuccessful. With one hour cycles, the conversion of 16 by 6a-TiO2 decreased by a factor of two with each successive cycle (see

Appendix A). Use of the more photostable 6b-TiO2 offered no improvement with a similar loss in reactivity after the first cycle. Catalyst bleaching was observed in every case. Acridinium 6a

Scheme 2.8: Limited catalytic activity of surface anchored acridinium. was also immobilized on silica gel and evaluated in this reaction. Although high conversion was observed in short reaction time, attempts to recycle the catalyst displayed a similar loss in reactivity with each cycle. Catalyst bleaching was also observed in these reactions.

Attempts to expand the substrate scope of the reaction with the 6a-TiO2 were met with surprisingly limited reactivity. Less than 2% conversion was observed in all cases, even at extended reaction times (Scheme 2.8). Particularly surprising is the lack of reactivity for the eugenol-derived substrate 14, since it is merely the alkene regioisomer of 16.

Romero and Nicewicz have previously demonstrated the existence of a preassociation complex between acridinium and styrenes.23 The lack of conversion of 14 may suggest that the observed reactivity of 16 occurs via a similar preassociation of catalyst and substrate. To probe this possibility, styrene 15 (starting as the Z-isomer) was submitted to the reaction conditions.

The presence of some conversion (ca. 10% after 4.5hr), albeit moderate, is consistent with the hypothesis that reactivity occurs through a preassociation complex. However, further investigation is necessary to demonstrate this conclusively.

2.2.7 Photophysical Investigations of Solid-Supported Catalysts

In order to further investigate the anomalous lack of reactivity, photophysical characterizations of the solid-supported acridinium catalysts were performed. In dichloromethane

27 solution, 6a shows simple mono-exponential decay of fluorescence with a lifetime of 6.9ns. This lifetime is very comparable to the lifetime of 9-mesityl-10-methylacridinium tetrafluoroborate

(12). However, upon attachment to the metal oxide surfaces, the fluorescence lifetime drops significantly and can no longer be fit to a simple mono-exponential decay. The complicated decay profile is not entirely unexpected. Photo-luminescence decay of metal-oxide supported chromophores are frequently fit to a stretched exponential function to account for various surface

78 heterogeneities. However, fluorescence decay of 6a-TiO2 required a stretched bi-exponential fitting, suggesting the existence of two distinct surface bound species. Additionally, the lifetime of each component was found to be heavily quenched relative to the fluorescence lifetime in solution.

Looking at the fluorescence lifetime as a function of catalyst loading, we noted a consistent decrease with increasing surface coverage. At low surface coverages, the fluorescence decay could effectively be fit to a single stretched exponential function. The lifetime of this species corresponds well with the longer-lived species previously observed from the slide at high loadings. Nevertheless, even at low surface coverages, the lifetime of the catalyst is highly quenched relative to the solution phase.

Vanillin-derived thiocarbamate 13 effectively quenches 6a in solution with a Stern-

9 -1 -1 Volmer quenching constant of kq = 7.5 x10 M s . However, upon attachment of 6a to TiO2, no fluorescence quenching by 13 is observed (see Appendix A). It is proposed that the highly quenched nature of 6a-TiO2 precludes electron transfer with 13 and hence subsequent reactivity.

On the other hand, fluorescence quenching of 6a-TiO2 is observed in the presence of 16, corresponding well with the observed reactivity. These results are consistent with a proposed

Figure 2.4: (A) Fluorescence decay of 6a in DCM solution (blue) and anchored on TiO2 (red). (B) Stern-Volmer quenching analysis of 6a-TiO2 at low surface coverage with increasing concentration of 16 as quencher.

Scheme 2.9: Synthesis of catalyst 19 bearing a long alkyl tether. preassociation complex between 16 and 6a-TiO2. In this way, productive electron transfer events may still occur despite the highly quenched nature of the catalyst excited state.ix

Several attempts were made to understand the photophysics of the surface-bound catalyst.

We hypothesized that the high degree of quenching could be due (A) to the proximity of the catalyst to the metal oxide surface (i.e. a surface interaction), (B) to aggregation caused by polysiloxane formation, or (C) to photoinduced single electron oxidation (i.e. hole injection) of the metal oxide.

ix Further evidence that reactivity may occur via a preassociation complex comes from reactivity of catalyst A1 (see Appendix A) which has tert-butyl substituents at the 3- and 6-positions of the acridinium core. Although the fluorescence lifetime of A1-TiO2 is extended compared to 6a-TiO2, conversion of 16 is significantly reduced consistent with disruption of the preassociation complex by the tert-butyl groups. See Appendix A for further details.

To address the possibility of a surface interaction, we initially synthesized catalyst 19 containing a long alkyl tether designed to displace the catalyst from the metal oxide surface

(Scheme 2.9).Very high photostability of 19 was observed, showing essentially no desorption or decomposition over 8 hours of irradiation. However, the excited state lifetime of 19-TiO2

(0.97ns) was found to be similarly quenched compared 6a-TiO2. Not surprisingly, 19-TiO2 showed no conversion of 13 while still displaying moderate conversion of 16.

The highly quenched excited state of 19-TiO2 may be explained by a number of factors.

Owing to the flexible nature of the alkyl tether, it was not possible to fully confirm that the catalyst was actually removed from the metal oxide surface. The possibility of the tether to bend back upon itself would allow for close contact between the surface and acridinium. The long alkyl chains might also make 19 more prone to aggregation than 6a. Alternatively, the lack of improvement in fluorescence lifetime could also be attributed to the significant increase in rotational freedom.

To ensure that the reaction center was separated from the surface, catalyst 22, featuring a rigid spacer, was synthesized, but showed no improvement in the excited state lifetime. The fluorescence decay required a stretched bi-exponential fit where the longest lived component had a lifetime of 3.0ns. Although a catalyst-surface interaction cannot be definitively ruled out, these results suggest that the observed lifetime limitation may be the result of an alternative quenching pathway.

Figure 2.5: Fluorescence decay traces (at 515nm) for catalysts 22 and 23 compared to solution phase decay of 6a.

Polysiloxane formation is known in the literature79 and thus it seemed reasonable that aggregation of catalyst molecules on the TiO2 surface could be through siloxane bridges. The ideal binding geometry of trisiloxanes is reported to involve only two silyl ether linkages, leaving one free.72,80 To preclude the possibility of polysiloxane formation on the surface, we prepared catalyst 23, bearing a monosiloxane anchoring group. Loading of 23 onto TiO2 was more difficult to achieve, but moderate loadings could be achieved via extended loading times.

Nevertheless, no improvement in the fluorescence lifetime was observed and stretched bi- exponential fitting of the decay profile was required. Additionally, a decrease in the excited state lifetime with increasing catalyst loading was once again observed. These results indicate that quenching of the excited state catalyst is not primarily due to the formation of polysiloxane aggregates. Catalyst aggregation on the metal oxide surface cannot be entirely ruled out as the cause of the short fluorescence lifetime, but it may be concluded that any such aggregation does not occur via polysiloxane formation.

Finally, we examined the possibility of photoinduced hole injection into the metal oxide valence band. The majority of photoinduced redox processes on metal oxide thin films involve

81,82 electron injection into the conduction band, particularly on TiO2. Hole injection is well established on p-type semiconductor materials such as nickel oxide where the valence band edge

83–86 is low lying (< +1.0 V vs SCE). However, reports of hole injection on TiO2 are extremely rare.87,88 This is primarily due to the highly positive potential of the valence band (VB) edge (ca.

2.44-2.69 V vs. SCE at pH = 7).89,90 For hole injection to be feasible, the excited state reduction

∗ potential (퐸푟푒푑) of the surface bound catalyst must ideally overlap with the VB edge. Upon

∗ ∗ examination, although 퐸푟푒푑 of 6a is highly positive (퐸푟푒푑 = +2.22 V vs. SCE), there remained a

200-300 mV gap (4.6–6.9 kcal/mol) between this potential and the lowest estimated position of the valence band edge. Additionally, the valence band edge for zirconia (ZrO2) is estimated to lie at significantly higher potentials (> +3 V vs. SCE) and yet similar photophysics are observed for

91 the catalysts on ZrO2 as on TiO2. For these reasons, the possibility of hole injection on the metal oxide surface was initially dismissed as unfeasible.

Nevertheless, after exhausting other alternatives, we returned to examine the possibility of hole injection in more detail. Guo and coworkers have reported hole transport in amorphous

92 TiO2 via a defect which lies at a potential 1.32 V less positive than the valance band edge.

Several other groups have also reported defects on nanocrystalline TiO2 that might lie below the valence band.93–95 Additionally, the exact value of the valence band edge is highly dependent on solvent, pH, polymorph, and preparation method. All of these factors suggest that surface defects or tailing of the VB edge might possibly overlap with the excited state redox couple of the supported catalyst.

To confirm hole injection on TiO2 thin films, the photophysics of the surface-bound catalyst were monitored as a function of externally applied bias. This experiment has been used in systems where electron injection is the dominant process.96–99 Applying a negative potential

Figure 2.6: Fluorescence lifetime of 6b-TiO2 as a function of applied potential. The excited state redox couple of the catalyst is indicated by the dashed line (---). increases the accumulation of electrons in the conduction band states and thus retards electron injection kinetics. A corresponding increase in excited state emission may be observed. For hole injection, the situation is reversed. Application of positive bias should deplete electron density in the valence band, essentially raising the VB edge, and limit or entirely preclude hole injection. A plot of the fluorescence lifetime of 6b-TiO2 vs. applied potential is shown in Figure 2.6. The results are consistent with hole injection. With increasing potential, the catalyst excited state lifetime steadily increased to a factor of 1.9 at +2.4 V. The results were found to be highly reversible. After application of +2.2 V, a slightly negative potential of −0.3 V was applied and the lifetime was returned closely to the original value. Visual inspection and UV-vis analysis of the film after applied potential confirmed high surface retention of the catalyst. These results support the conclusion that the photophysical changes are due only to redox manipulations of the metal oxide and not chemical alteration of the surface bound catalyst. Thus, after careful investigation, the highly quenched photophysics of the surface-bound catalysts may be attributed in part to photoinduced hole injection into the metal oxide valence band.

Figure 2.7: Fluorescence lifetime decay traces (at 515nm) for carboxylate anchored catalysts on ZrO2 and comparison to siloxane anchored catalyst.

However, hole injection does not appear to entirely account for the highly quenched surface photophysics. This is illustrated by the fact that applying a potential significantly above the excited state redox couple of the catalyst does not result in full return of the lifetime relative to solution phase measurements. Instead, we suggest that the siloxane anchoring group also contributes in some manner to excited state quenching. The exact nature of this contribution is currently unknown, but is believed to result from interaction of the siloxane with the metal oxide, since similar quenching is not observed in free solution. The effect of the siloxane anchoring group is clearly illustrated by comparison of 6a-ZrO2 with a series of carboxylate anchored catalysts on ZrO2 (Figure 2.7). Acridinium 24 exhibits high quenching attributed to efficient hole injection. Catalyst 25, containing a simple methylene insertion, shows retardation in hole injection with significantly extended lifetime on the surface. Finally, use of a fully saturated linker in catalyst 26 precludes hole injection entirely, resulting in solution-like photophysics.

Comparison of 26-ZrO2 and 6a-ZrO2, both of which contain only saturated aliphatic tethers, clearly demonstrates the non-innocence of the siloxane.

2.3 Conclusions

We have reported our progress towards the development of metal oxide supported acridinium photocatalysts. Synthesis and surface attachment of several different acridinium photocatalysts bearing siloxane anchoring groups was achieved. The presence of oxygen in the system was found to be detrimental to surface stability under irradiation. Rigorous exclusion of oxygen resulted in excellent photostability over several hours. The catalytic behavior of the surface-bound photocatalyst was examined in a photoredox-mediated Newman-Kwart rearrangement. Moderate to good conversions were observed for styrenyl substrates which are suggested to undergo preassociation with the catalyst. Catalyst bleaching was observed during the reactions, thus limiting catalyst recyclability. In contrast to solution phase reactivity, extension of the reaction to non-styrenyl substrates resulted in no appreciable levels of conversion. Photophysical measurements revealed severe quenching of the catalyst excited state lifetime upon surface attachment. Upon careful examination, quenching is attributed in part to siloxane-assisted hole injection into the metal oxide valence band. Additional quenching is attributed to further non-innocence of the siloxane anchoring group, although the specific interaction remains unclear. Solution-like photophysics could be achieved on the metal oxide surface for an acridinium bearing a carboxylate anchoring group on a fully saturated tether.

2.4 Future Work

Future work will examine stabilization of acridiniums bearing carboxylate anchoring groups on the metal oxide surface and evaluation of their reactivity. Additionally, given the rare nature of hole injection on TiO2 and ZrO2, further investigations of these photophysical processes will be conducted. The role of the siloxane anchoring group in hole injection and excited state quenching should also be examined in greater detail.

2.5 Acknowledgements

I would like to acknowledge my collaborator Prateek Dongare for help with all of the initial photostability measurements. I would like to thank Dagao Wang for graciously supplying us with the metal oxide films. I would particularly mention M. Kyle Brennamen for his help in photophysical measurements. I could not have done this without his guidance and assistance. I would like to thank Kevin Olson for his help in collecting IR spectra and for many encouraging conversations. I also thank Michael Mormino for generous donation of catalyst 26. This research made use of instrumentation (Edinburgh FLS920 Spectrometer, Cary50 UV-vis spectrophotometer, and Cary5000 UV-vis spectrophotometer equipped with an integrating sphere) funded by the UNC EFRC: Center for Solar Fuels, an Energy Frontier Research Center supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences

(DESC0001011).

CHAPTER 3: OXIDATION OF ALKYL BENZENES BY A FLAVIN PHOTOOXIDATION CATALYST ON NANOSTRUCTURED METAL-OXIDE FILMS Reproduced with minor edits with permission from Dongare, P.; MacKenzie, I.; Wang, D.; Nicewicz, D. A.; Meyer, T. J. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 9279-9283. Copyright 2017 belongs to the authors.

3.1 Introduction

An important element in synthetic organic chemistry has been the development and application of organic excited states in solution, either by sensitization or electron transfer catalysis.2 Exploitation of organic excited states has evolved from the bench scale to the photochemical reactor scale. In a parallel effort, with a different focus, advances have also been made in exploiting nanoparticle oxide surfaces for energy conversion applications based on chemically bound molecular reactants.56 An advantage of the latter is maximization of the local microscopic surface volume for enhancing efficiencies. We describe here the integration of the two areas with the goal of creating stable photochemical environments that minimize reaction volumes in photooxidation reactions.

Our experiments exploit the excited states of the flavin cofactors found in riboflavin

(vitamin B2), flavin mononucleotide (FMN), and flavin adenine dinucleotide. They are potent photocatalysts and play important roles in biological reactions.33,39,100,101 In its redox properties,

FMN is more flexible than nicotinamide adenine dinucleotide (NAD) as a donor because it can participate in either 1e− or 2e− transfer reactions (Eq. 1) as opposed to NAD, which undergoes

2e− hydride transfer.34,102,103

Analogous to quinones, FMN can exist in three redox states––oxidized (flavin-quinone), one-electron reduced (flavin-semiquinone), and two-electron reduced (flavin-hydroquinone).102

Riboflavin-based organocatalysis has been explored as a green and economic alternative to metal catalyzed reactions32 in the photooxidation of alkyl benzenes, amino acids, phenols, saccharides, water, and other substrates.38–40,104–108

In the current study, we have explored an FMN photocatalyst bound to nanoparticle transparent metal-oxide surfaces in the C–H oxygenation of alkyl benzenes. The FMN derivative consists of the iso-alloxazine, ribityl, and phosphate groups as shown in Figure 3.1. In the absence of external electron transfer donors, the ribityl group undergoes intramolecular photooxidation, reducing the iso-alloxazine and rendering the riboflavin photosensitive. In the current application, the phosphate group also serves to bind the FMN dye to oxide surfaces.

Figure 3.1: Structure of flavin mononucleotide (Left) and the surface-bound FMN assembly (Right) on the surface of ZrO2 or TiO2.

The photophysics and photooxidation of the flavins have been investigated earlier.41

Upon irradiation with blue light, the FMN chromophore forms a lowest-energy singlet-excited state (1FMN) with high efficiency. It is a potent oxidant with an excited-state reduction potential

(FMN*/FMN−•) of +1.77 V vs. saturated calomel electrode with the ability of oxidizing substrates with potentials <1.8 V.109 In the photooxidation of alkyl benzenes, Megerle et al. have reported that electron transfer (ET) occurs from the triplet state, 3FMN,110 accessed after rapid intersystem crossing (7.8 ns in water).41 ET to 3FMN, or proton-coupled electron transfer

111 (PCET), oxidizes the alkyl aromatic substrate within 6 μs in 1:1 vol/vol H2O/MeCN to give a

41 dihydroflavin intermediate (FMNH2). FMNH2 is subsequently reoxidized to the ground state with oxygen as the terminal oxidant.108,112,113 A mechanism analogous to methoxybenzyl alcohol

41 oxidation by riboflavin tetraacetate in 1:1 vol/vol H2O/MeCN by Megerle et al. is shown in

Eqs. 2–4.

In an alternate pathway, formation of an alkyl benzene radical in the presence of oxygen has the capability to initiate radical chains, as the peroxyl radicals are very reactive with their corresponding alkyl benzene form. As pointed out earlier, there is a possibility of contributions in overall catalysis from competitive pathways.114 However, the mechanistic details for the reactions cited here remain to be established in detail, but there is evidence for the involvement of multiple pathways including a possible role for PCET.111,115 A putative mechanism is shown in Scheme 3.1.

Scheme 3.1: Generalized mechanism for the photooxidation of benzyl alcohol as a representative substrate by an FTO|ZrO2-FMN surface in the presence of O2.

The reactivity of flavins, incorporating oxygen as both a reactant and terminal oxidant, makes them good catalysts in aerobic environments. Paradoxically, the use of O2 as an oxidant in

108,116 these reactions poses a problem because H2O2 is an intermediate and is known to cause degradation of the flavin cofactor resulting in low reaction yields and poor selectivities.40

To circumvent H2O2 as an intermediate, a number of strategies have been explored including the use of transition-metal disproportionation cocatalysts,40,117 surfactants,37 modification of the flavin,34 and others.38,118,119 Mühldorf and Wolf40 recently added a nonheme iron complex, [Fe(TPA)(MeCN)2](ClO4)2 (TPA = Tris(2-pyridylmethyl)amine) as the

117 cocatalyst for the disproportionation of H2O2 (2H2O2→O2+2H2O) with notable increases in

40 efficiencies for the photooxidation of alkyl benzenes to ketones and carboxylic acids.

Experimental evidence suggested that the increased activity could be attributed to efficient disproportionation of H2O2 with a contribution from higher oxidation states of Fe(TPA) in the C–

H photooxygenation of the alkyl benzenes.

Extension of the flavin photochemistry to inert surfaces remains largely unexplored.

There are examples of flavins immobilized on silica39 and attached to a polystyrene copolymer120. However, systematic exploitation of surface binding and flow-through reactors could provide significant synthetic advantages.121 Surface binding to inert, mesoporous oxides minimizes catalyst loading and reaction volumes and subsequently simplifies the reaction conditions and product workup. With transparent metal-oxide supports, a variety of surface- coated reactor designs are available which would be difficult or impossible to achieve with more conventional supports based on silica or polymer beads. In homogeneous catalysis, solubility can also play a major role in the efficiency of a reaction. The majority of the results in the literature on flavin-mediated photooxidations use riboflavin tetraacetate rather than FMN as the photocatalyst because of a gain in catalyst solubility. In heterogeneous catalysis, solubility is no longer a primary factor, allowing the surface-bound FMN to be used with good efficiency.

We report here data on surface binding, stabilization, and reactivity of a phosphate- bearing FMN on high surface area, nanoparticle metal-oxide surfaces. As an example, research in this area has resulted in oxide surfaces that have found applications in photoelectrochemical water splitting.56 Techniques are available for preparing optically transparent, nanoparticle surfaces with dimensions in the tens of micrometers with absorptivities sufficient to drive photochemical reactions with high efficiencies even with intense light sources.56 In the experiments described here, 4-μm films of 10-nm nanoparticles of ZrO2 or 15–20 nm of TiO2

41 nanoparticles on fluorine-doped tin oxide (FTO) were added to coated glass substrates (1.0 cm2).

Subsequent addition of the dye to the surface gave films of FTO|ZrO2|-FMN or FTO|TiO2|-FMN.

3.2 Results and Discussion

A series of experiments were undertaken to explore the surface properties of the bound dye (Table 3.1 and Appendix B SI Methods). Catalyst loading used techniques developed for related photoelectrodes.56 Oxide slides were loaded in 0.5 mM methanol solutions of FMN for up to ∼6 h to achieve the highest surface loadings. The highest surface coverages under these conditions were Γ = 5.7 × 10−11 mol cm−2.122 By way of comparison, loading of the metal-to-

2+ ligand charge-transfer chromophores [M(bpy)2((4,4′-PO3H2)2bpy)] (M = Ru, Os, bpy = 2,2′- bipyridine, and 4,4′-(PO3H2)2 bpy = 4,4′-bis-(phosphonic acid)-2,2′-bipyridine) under the same conditions result in coverages of ∼10−10 mol/cm2. Fig. B.1 shows the absorption spectrum of a

−11 −2 fully loaded FTO|ZrO2|FMN film with a loading of Γ = 5.7 × 10 mol cm in 1:1 vol/vol

MeCN/H2O.

In the 4-μm films of the oxides used here, the absorption spectrum of the adsorbed dye at its λmax of 450 nm is 0.9. For these high surface area oxide films, the ratio of internal to geometric surface area was ∼200. The highest catalyst loading was calculated to be ∼1.1 × 10−8 mol (<0.02 mol%).

Following surface binding, a major challenge in photocatalytic applications was the stability of the oxide-bound catalyst.73 Upon irradiation with visible light (3-W blue LED, 440

123 nm) in 1:1 vol/vol MeCN/H2O, the FMN catalyst desorbed from the surface (Fig. 2, red trace), leading to diminished reactivities. To address issues of surface stability, we performed a series of photostability measurements on modified ZrO2 and TiO2 metal-oxide surfaces by time-dependent spectral monitoring of the FMN catalyst at 450 nm (Fig. B.2).

Stabilities were assessed by varying solvent polarity in both nitrogen and oxygen atmospheres under LED irradiation. Under most conditions, the catalyst showed full desorption in ∼30 min (Fig. B.2). To address the surface stability issue, we attempted to stabilize surface binding on FTO|ZrO2|-FMN or FTO|TiO2|-FMN by using a thin coating of a poly(methyl methacrylate) (PMMA) overlayer as described elsewhere for a Ru(II) polypyridyl dye.124

Addition of PMMA did result in greatly increased FMN stability on the oxide surface.

Unfortunately, the PMMA layer was unstable in organic solvents and its application was limited to water.

To stabilize FMN on the surface, we used atomic layer deposition (ALD) to coat the derivatized surfaces with a thin 1.0-nm overlayer of Al2O3. The ALD procedure resulted in significant enhancements in stability, for periods of up to ∼3 h (Figure 3.2, black). ALD has been used extensively for stabilizing chromophores and chromophore–catalyst assemblies on the surfaces of dye-sensitized photoelectrosynthesis cells for water splitting.56,125

Figure 3.2: Spectral changes with time at 450 nm following irradiation of 1.0-cm2 films loaded with 4-μm-thick FTO|ZrO2|-FMN films either stabilized with ALD with a 1.0-nm overlayer of Al2O3 (black) or unstabilized (red). The data were obtained in 1:1 MeCN/H2O (vol/vol).

With the ALD stabilization of FMN established, a platform was available for exploring

C–H photooxidation of alkyl benzenes on the oxide films. Selecting the conversion of benzyl alcohol to benzaldehyde as a model reaction (Eq. 5), we explored a variety of conditions with results shown in Table 3.1; in a series of control experiments, we explored the impact of reaction conditions in 1:1 H2O:MeCN. Variations with light intensity, O2, and an added cocatalyst were all explored, which ruled out adventitious photooxidation. Based on these experiments, in the absence of FTO|ZrO2|-FMN, a ZrO2 surface was unreactive. In homogeneous solutions with added FMN, conversions were lower by a factor of ∼2 compared with the heterogeneous reactions in part due to the limited solubility of the dye, an additional advantage of the surface- bound reactant.123

Table 3.1. List of control experiments with benzyl alcohol to benzaldehyde as the model reaction

Entry Condition t, h Yield, %

1 FTO|ZrO2-FMN/O2/MnO2/blue LED 2.5 64 2 FMN/O2/MnO2/blue LED 2.5 31 3 No ZrO2-FMN 2.5 1 4 No O2 2.5 3 5 Dark 2.5 0 6 Bare ZrO2 2.5 4 7 No cocatalyst (MnO2) 2.5 16

The reactivity of the adsorbed dye on FTO|ZrO2|-FMN was explored for the substrates shown in Table 3.2 using the blue LED with 0.06 mmol of substrate and 8 mol % of added MnO2 or [Fe(TPA)(MeCN)2](ClO4)2 (Table S1), in 1:1 H2O:MeCN (vol/vol). Further experimental details are provided in SI Methods.

Table 3.2. Substrates for photooxidation by FTO|ZrO2|-FMN with added MnO2 cocatalyst, their corresponding products, reactions times, and product yields in 1/1 H2O:MeCN (vol/vol)

* Standard conditions: 0.06 mmol substrate, 8 mol % MnO2, 1.5 mL 1:1 H2O:MeCN vol/vol, O2 saturated, LED (3 W, 450 nm). † Yields were determined using NMR with hexamethyldisiloxane (HMDSO) as an internal standard. ‡ Obtained with added 30 mol % HClO4.

Benzyl alcohol and 1-phenylethanol were converted to the respective aldehyde and ketone in good yields (Table 3.2, entry 1). The substituted toluene and ethylbenzene derivatives gave the corresponding aldehydes and acetophenones in good yield (entries 2 and 3).

Isochroman, indane, and fluorene (entries 4–6) were all converted into their ketones in moderate to good yields. Xanthene and thioxanthene generated xanthone and thioxanthone in excellent yields (entries 7 and 8) and, for thioxanthene, very short reaction times. Substrate 4- methoxybenzyl methyl ether yielded the benzyl ester in high yield (entry 9). The conversion of tolane to benzil occurs (entry 10), but in reduced yield similar to the corresponding homogeneous reaction.105 Additionally, trans-stilbene (entry 11) underwent photooxygenation to yield benzaldehyde in good yield. A representative set of NMR data is presented in Figs. B.3–

B.5.

We also investigated FTO|TiO2|-FMN surfaces to explore the role of the oxide surface on reactivity. In the comparative experiments, the product yield was largely the same between oxides. Although no attempt was made in the reaction sequence to exploit the known redox reactivity of TiO2, given its accessible conduction band (CB) at ECB ∼0 V vs. normal hydrogen electrode, there was no evidence for its involvement in surface reactivity of the dye.123 The latter could be an issue with other reactions, but is of less importance for films of FTO|ZrO2|-FMN given its 0.5-V-higher CB potential for ZrO2.

We examined the effect of the deuterated version of the solvent on product yield to rule

126 1 out participation by singlet oxygen. Given its known reactivity, O2*, formed by energy

3 3 3 1 127 transfer to O2, FMN∗ + O2→ O2∗ + FMN, could play a significant role under our conditions.

Since the lifetime of singlet oxygen is extended in the deuterated version of the solvent,128 we investigated the oxidation of ethylbenzene, FTO|ZrO2-FMN, with added MnO2 for 1 h in 1/1

D2O/CD3CN (vol/vol). Analysis of the products gave a conversion yield of ∼56%, compared with 67% for the nondeuterated solvent 67% (Table 3.2). In a second experiment, the known singlet oxygen sensitizer, Rose Bengal, was used (10 mol %, 0.01 mmol, 9.7 mg) with benzyl alcohol (0.1 mmol, 10.4 μL) in 7.5 mL of 1:1 vol/vol H2O/MeCN. Oxygen was continuously bubbled through the solution while irradiating with green light (520-nm LEDs) for 2.5 h. There was no evidence for the hydrocarbon oxidation product under these conditions.

3.3 Conclusions

We have demonstrated here a procedure for a minimum-volume, high-efficiency, organic photochemical reactor. It is based on a surface-bound, flavin-based chromophore on high surface area oxide films. This configuration provides a basis for stable photoredox catalysis in an ultrathin, high surface area nanoparticle reactor.

In the example investigated here, a phosphate-bearing flavin mononucleotide dye was bound to high surface area ZrO2 or TiO2 films with surface stabilization by ALD. The modified metal-oxide films demonstrated excellent catalytic activity following irradiation with a 440-nm blue LED. The experiments demonstrate the viability of the approach, one that could be of general value in organic photochemical reactions under conditions that minimize reaction volumes and the time for reaction workup.

For the FMN reactions, the reactivity of the dye on the high surface area oxide films was maintained with high yields obtained for a series of hydrocarbon oxidations. The results presented here provide a basis for extension to larger scales and to catalyst–oxide assemblies with potential applications for larger-scale organic reactions.

3.4 Methods

Detailed spectral data and analysis are included in Appendix B.

3.5 Acknowledgements

We thank Prof. Chris Dares for help with the reaction setup and preliminary data collection. This research was supported by National Science Foundation Grant CHE-1362481.

CHAPTER 4: STRONGER THAN LITHIUM: PHOTOEXCITED ACRIDYL RADICAL AS A SUPER-REDUCTANT FOR SINGLE ELECTRON REDOX CHEMISTRY

4.1 Introduction

Conversion of light into chemical energy for small molecule activation has been known and examined for the past century.1 However, it is only in the last decade that the use of visible light for sensitized photocatalysis has been widely exploited.2–4,129 A large variety of new reaction methodologies have been developed, taking advantage of energy transfer (EnT) and single electron transfer (SET) pathways mediated by simple organic dyes or organometallic complexes. In particular, the latter pathway has received much attention due to the generation of highly reactive radical intermediates.

The thermodynamic feasibility of an electron transfer process is governed by the redox potentials of the species involved.2 When an organic or organometallic photocatalyst absorbs a photon of light, it becomes a much stronger oxidant or reductant in the excited state than in the ground state. This may be expressed in the following equations:

∗ 퐸푟푒푑 = 퐸푟푒푑 + 퐸exc (1)

∗ 퐸표푥 = 퐸표푥 – 퐸exc (2)

∗ ∗ where 퐸푟푒푑 and 퐸표푥 are the excited state redox potentials, 퐸푟푒푑 and 퐸표푥 are the ground state

x potentials, and 퐸exc is the energy of the excited state from which electron transfer occurs.

However, because photoredox catalysts are typically bench stable species, the ground state redox

x Eexc is commonly assigned as E0,0 for the energy of the lowest excited state (singlet or triplet). However, as demonstrated later, this assignment is not appropriate when electron transfer occurs from a higher excited state.

49 potentials are thermodynamically unfavorable (i.e. Ered is negative, Eox is positive) and thus subtract from the excited state energy. An additional challenge is the energy limitation of the incident light. For example, a single photon of 440 nm blue light contributes a maximum of 2.8 eV to the excited state energy in the theoretical case of zero Stokes shift. In actuality, energy loss due to reorganization and intersystem crossing is often significant (~0.8 eV for Ru complexes).130 The combination of energy loss due to ground state redox potential and excited state reorganization has thus far limited the oxidizing and reducing power of closed shell, visible

∗ ∗ 2 light photoredox catalysts (ca. 퐸푟푒푑 ≤ +2.5 V vs. SCE, 퐸표푥 ≤ −2.5 V vs SCE).

Phenothiazine is a class of highly reducing photoredox catalysts with absorption typically in the UV region of the electromagnetic spectrum.131 Christensen and coworkers have recently

132 reported the photophysical properties of stable phenothiazine radical cations. 퐸푟푒푑 for these open-shell species is thermodynamically favorable and thus additive to 퐸exc. As a result, upon visible light excitation, the phenothiazine radical cation is characterized as a super-oxidant with

∗ 퐸푟푒푑 as high as +2.9 V vs. SCE. Taking inspiration from this work, we were interested in studying the photophysical properties of other stable radical species.

Our group has developed a wide array of light-mediated transformations enabled by the high excited state reduction potentials of acridinium photooxidants.27,133–137 During our studies we have observed, as has been reported by others, that single electron reduction of 9-substituted acridinium salts resulted in stable acridyl radical species.11,138 Photoexcitation of open shell organic intermediates is relatively rare, but has been reported in some cases to have a significant effect on catalysis.139,140 Here we report an investigation of the photophysical and catalytic properties of 3,6-ditertbutyl-9-mesityl-10-phenyl acridyl radical (1).

Figure 4.1: (A) Absorption spectra of acridinium 2 and acridyl radical 1. (B) Excitation wavelength dependent emission spectra of 1.

4.2 Results and Discussion

Acridyl radical 1 could be easily generated upon reduction of 3,6-ditertbutyl-9-mesityl-

10-phenyl acridinium tetrafluoroborate (2) with bis(cyclopentadienyl) cobalt(II). In the absence of oxygen, 1 is indefinitely stable in solution and is well characterized by EPR (Appendix C, figure C.1). Analogous to the Christensen work, the ground state redox potential of 1 is thermodynamically favorable (퐸표푥 = – 0.60 V vs SCE) as determined by cyclic voltammetry. The absorption spectrum of 1 presents two main features, a low energy absorption near 520nm which is red shifted relative to the parent acridinium, and a high energy absorption centered at 360nm

(Figure 4.1a). Analysis of the emission spectrum of 1 yielded surprising results (Figure 4.1b).

Upon excitation of the higher energy absorption, emission was observed at a higher energy than the absorption maximum of the lower energy band. This type of emission is described as Anti-

Kasha’s Rule emission since it does not occur from the lowest energy excited state.141 This phenomenon is relatively rare because internal conversion (IC) and vibrational relaxation (VR) processes generally occur on a much faster time scale than emission. However, if nonradiative relaxation to the lowest energy excited state is retarded, then wavelength dependent emission

Figure 4.2: (A) Spectral deconvolution of the excited state emission of 1 upon excitation at 385nm. (B) Normalized absorption, emission, and excitation spectra of 1. may be observed. Common cases of this type include intersystem crossing (ISC) promoted from higher excited states, a large Sn – S1 energy gap, or intramolecular charge transfer upon photoexcitation.141

Further analysis of the photophysical properties revealed the existence of two distinct emissive excited states. Excitation of the low energy absorption resulted only in mirror like emission at lower energy. This emission was also observed upon excitation of the high energy band, but with the addition of the high energy emission feature. Spectral deconvolution, fitting the high energy feature to a Gaussian distribution, allowed separation of the two components

(Figure 4.2a). The excitation spectrum of 1 confirms that the excited state responsible for the anomalous emission occurs at a higher energy than the lowest energy absorption (Figure 4.2b).

Assignment of the excited state features is assisted by experiment and significant literature precedent.141–146 Scuppa and coworkers have recently demonstrated Anti-Kasha’s Rule fluorescence as the result of a twisted intramolecular charge transfer (TICT) state in (2-

Ferrocenyl)indene complexes.146 After excitation to this state, the orthogonal nature of the indene fragment prevented fast relaxation to the lowest energy local excited state. An analogous TICT

Figure 4.3: (A) Excitation wavelength dependent emission of 3. See Appendix C for further details. (B) Excitation spectra of 3 collected at varying emission wavelengths. state is proposed in the present system. Upon high energy excitation, charge transfer from the acridine core onto the mesityl ring is populated. The methyl groups in the 2- and 6-positions limit rotational relaxation and maintain orthogonality to the acridine core, thus giving rise to the observed anomalous emission by obviating (or at least significantly retarding) relaxation to the

D1 state. Experimental support for the proposed TICT state comes from emission studies with the related 9-terphenyl acridyl radical 3. Wavelength dependent emission from two distinct excited states is again observed upon photoexcitation (Figure 4.3, also see Appendix C). However, in this case the anomalous emission occurs at a lower energy than the normal D1 emission. This is consistent with the proposed TICT state where the arene radical anion populated upon charge transfer is significantly stabilized by delocalization throughout the terphenyl π-system. The high energy emission observed upon photoexcitation of 1 is thus tentatively assigned as resulting from a TICT excited state. As the TICT state is only accessible upon high energy excitation, low energy excitation results only in emission from the D1 state. A simplified Jablonski depiction of the photophysical processes of 1 and 3 is shown in Figure 4.4.

Figure 4.4: Plausible Jablonski depiction of the photophysical processes of 1 and 3. Excitation, non-radiative relaxation, and emission are represented by solid, wavy, and dashed arrows respectively.

The electronic energy of the D1 and TICT states of 1 were estimated to be 2.31 eV and

2.76 eV respectively (see Supporting Information for details). Using the ground state oxidation potential measured by cyclic voltammetry, the excited state oxidation potential of each state was calculated (D1 = -2.91 V vs. SCE; TICT = -3.36 V vs. SCE). It should be highlighted that not only is the TICT state more reducing than lithium, but the excited state oxidation potentials for both the D1 and TICT states are the highest yet reported for any small molecule upon visible light excitation.

Having characterized the extremely reducing nature of the excited states of 1, we next turned to examine its utility as a reductive photocatalyst. Reductive dehalogenation of aryl halides has served as a literature benchmark of catalyst reducing power.147–152 In particular, due to their highly negative reduction potentials, electron rich aryl bromides and chlorides have remained almost exclusively outside the range of visible light promoted photoreductants. With this in mind, we determined to focus on these substrates as a demonstration of the reducing power of 1.

Entrya X Light Source Yield (%)b 1 1.2 390nm 50 2 2.0 390nm 65 3 3.0 390nm 81 4c 1.2 390nm 0 5 - 390nm 0 6 1.2 450nm 0 Table 4.1: Initial optimization of reductive dehalogenation. aConditions: All reactions were conducted in a 1 dram vial equipped with stir bar under air with 0.1 mmol substrate, 0.01mmol catalyst, 0.12–0.30mmol N,N-diisopropylethylamine (DIPEA) and 0.3ml acetonitrile. bYields determined by 1H NMR using 3.5μl hexamethyldisiloxane (HMDSO) as internal standard. cReaction run in the absence of 2.

Considering that pre-generation of the acridyl radical with cobaltocene is non-ideal, we envisioned that 1 could be generated in situ from reaction of excited state acridinium 2 with a sacrificial electron source. This was easily demonstrated by irradiation of 2 with 450nm LEDs in the presence of N,N-diisopropylethylamine (DIPEA). Full conversion to 1 is rapidly observed (tirr

< 1 minute) although in this case 1 is no longer indefinitely stable and is reoxidized to 2

(presumably by the amine radical cation) over the course of several minutes (Figure C.7).

Reaction optimization began with 1-bromo-4-tert-butylbenzene (4a) as substrate with DIPEA as the stoichiometric electron source (Table 4.1). Irradiation with 390nm LEDs allows for single source excitation of both 2 and 1 with population of the higher excited state of the radical. In acetonitrile solution, a modest yield of 50% tert-butylbenzene was observed after irradiation with

1.2 equivalents of DIPEA. Proton NMR indicated full consumption of the amine during the reaction and upon increasing the equivalents of DIPEA the yield of protodehalogenation was increased to 81%. Control reactions in the absence of catalyst or amine gave no conversion.

a a Substrate 퐄퐫퐞퐝 (vs. SCE) Yield (390nm) Yield (467nm) 4b < – 2.7 Vb 90% 0% 4c −2.06 V 78% 34% 4d −1.58 Vc 72% 49% Table 4.2: Wavelength dependent reactivity of substrates of varying reduction potential under the optimized conditions from Table 4.1. aYields determined by 1H NMR with HMDSO as internal standard. bNo reduction observed within the MeCN solvent window. cReduction potential from reference 153.

Interestingly, irradiation with 450nm LEDs also resulted in no product formation. This may be attributed to negligible population of the TICT state of 1 at this wavelength. The reduction potential of this substrate has not previously been reported and upon analysis by cyclic voltammetry, no reduction wave was observed within the electrochemical window of acetonitrile

(ca. – 2.7 V vs. SCE). As a result, reduction of 4a from the D1 state may possibly lie uphill or be prohibitively slow due to a low driving force for electron transfer. The marked reactivity dependence upon excitation wavelength highlights the significant energy difference between the two excited states and may prove valuable for chemoselective reductions.

To further illustrate the reactivity differences of the two excited states of 1, three substrates of varying reduction potential were subjected to the reaction conditions at two separate excitation wavelengths (Table 4.2). Similar to the reactivity of 4a mentioned above, 4- bromoanisole (4b) is reduced only by population of the TICT state of 1, as a result of its highly negative reduction potential. Reduction of the less electron rich 4-chlorobenzonitrile (4c) and 4- bromobenzotrifluoride (4d) could be accomplished at either excitation wavelength. The increased yields at higher energy excitation may be attributed in part to population of both reactive excited states at this wavelength.

Chart 4.1: Substrate Scope of Reductive Dehalogenation Catalyzed by Acridinium 2.

Having established catalytic activity from both excited states of the acridyl radical, the scope of aryl bromide reduction was briefly evaluated (Chart 4.1). Very electron rich dimethoxy bromobenzenes (4e-4g) as well as bromoanisoles (4b, 4h) and bromothioanisole (4i) were reduced in good yields. Alkyl substituted bromobenzenes were well tolerated as well as the electron deficient 4-bromobenzoic acid (4j, 4k). For comparison, the reduction of 4- bromoanisole (4b) was also attempted using common organic and organometallic photoreductants. Less than 10% yield of anisole was observed when using N-phenyl- phenothiazine or Ir(ppy)3 catalysts.

Aryl chlorides are more prevalent in nature than aryl bromides, but are also less amenable to transition metal catalysis.154 In addition, aryl chlorides have higher reduction potentials than their bromide counterparts, making them even less accessible to traditional photoredox catalysts.152,155 Reduction of aryl chlorides under our standard conditions provided dehalogenation products in moderate yields. However, slight adjustment of the reaction conditions by increasing the substrate concentration to 0.5 M resulted in high yields. With these reoptimized conditions, we explored the substrate scope of aryl chloride reduction.

Chloroanisoles and biaryl ethers were reduced in high yields (5a-5e). Alkyl substituted chlorobenzene could be accessed with no indication of benzylic oxidation or functionalization

(5f). Electron deficient chlorobenzonitriles, 4-chlorobenzotrifluoride, and 2-chlorobenzoic acid were also competent substrates for this chemistry (4c, 5g-5i).

The broad functional group tolerance of this methodology should be highlighted.

Substituted pyridines and Boc-protected anilines were well tolerated (5j-5l). Free alkyl alcohols, alkenes, and ketones were also compatible (5m-5o). Of particular note is the tolerance of free alkyl carboxylic acids in this chemistry (5p). Light-mediated decarboxylation of alkyl carboxylic

Scheme 4.1: Reductive dehalogenation of poly-halogenated anisoles. Yields were determined by 1H NMR. acids catalyzed by acridinium has been previously reported.156 However, in the presence of

DIPEA as a competitive quencher, the decarboxylation pathway is completely restricted.

Application of this chemistry for the late stage modification of drug-like materials has also been demonstrated. Reductive dehalogenation of derivitized estrone (5q) proceeded in 58% yield.

Meanwhile, reduction of chloroarenes containing additional redox active functionality proceeded in generally decreased yields. Reduction of 2-chlorophenol proceeded in only 30% yield, presumably due to competitive single electron oxidation of the free phenol. Significant polymer formation was observed in the reduction of 4-chlorophenylacetylene, although free phenyl acetylene could be detected in 32% yield. Reduction of 2-chlorobenzoxazole was found to proceed in 46%, but with significant byproduct formation.

Reduction of multiply-halogenated compounds was also demonstrated (Scheme 4.1), showing possible application in the treatment of poly-halogenated environmental contaminants.

Reduction of 3,5-dibromoanisole under standard conditions gave anisole in 58% yield.

Additionally, reduction of 2,4-dichloroanisole generated anisole in 46% yield, with an additional

49% yield of 4-chloroanisole. Selectivity for the monoreduction can be rationalized by heteroatom stabilization of the aryl radical formed upon cleavage of the ortho C–Cl bond.

Figure 4.5: Structures of 9,10-dihydroacridine 6 and acridine anion 7.

In many of these reactions, catalyst deactivation to a stable off-cycle intermediate was observed. Upon closer examination, this species was identified as the 9,10-dihydroacridine (6)

(Figure 4.5). Direct formation of 6 from 1 is postulated to occur by abstraction of a hydrogen atom from the DIPEA radical cation formed upon photoreaction with 2. Alternatively, upon photoexcitation, the acridyl radical may effectively undergo a disproportionation by reduction of another equivalent of 1 to generate 2 and the acridine anion (7). Formation of 7 is also feasible by reductive quenching of the D1 or TICT states with DIPEA as both excited states are mild

∗ oxidants as well as potent reductants. 퐸푟푒푑 is calculated to be +0.67 V and +1.12 V vs. SCE for the D1 and TICT states respectively. Literature reports of the ground state oxidation potential of

157–161 DIPEA vary (퐸표푥= 0.63–0.83 V vs. SCE), but place it well below the excited state reduction potential of the TICT state. Protonation of 7 by solvent or trace moisture present in the reaction would result in the formation of 6.

Although the mechanism of this transformation is currently under investigation, a proposed catalytic cycle is shown in Figure 4.6. Upon excitation of 2 with visible or 390nm light, the catalyst enters a highly oxidizing singlet excited state. Single electron oxidation of DIPEA then generates 1 and the amine cation radical. Photoexcitation of 1 by absorption of a 390nm photon results in population of both the D1 and TICT excited states whereas absorption of a photon of lower energy (≥ 450nm) results in population only of the D1 excited state. For aryl

Figure 4.6: Proposed mechanism for reductive dehalogenation of aryl halides.

halides with reduction potentials more positive than -2.91 V vs. SCE, single electron transfer to the substrate occurs from both populated excited states. However, for more recalcitrant substrates, electron transfer occurs only from the TICT excited state. Upon reduction, an aryl radical anion is formed with concomitant regeneration of 2. Fragmentation of the aryl radical anion results in formation of an aryl radical intermediate. Hydrogen atom transfer from the amine cation radical or solvent furnishes the proto-dehalogenated product.

In order to determine the ultimate source of hydrogen atoms in these reactions, we performed the reduction of 4-bromoanisole in deuterated solvent (CD3CN). No deuterium incorporation was observed, indicating that DIPEA most likely acts as the hydrogen atom donor.

This is well precedented in the literature as it is reported that the BDE of alpha C–H bonds in

Scheme 4.2: Reductive dehalogenation and intramolecular cyclization of 8 under standard reaction conditions. Yield determined by 1H NMR. tertiary alkyl amines drops to ~42 kcal/mol upon single electron oxidation.162 However, we cannot definitively rule out trace water as the hydrogen atom donor in these reactions.

To further confirm that an aryl radical intermediate is generated during the course of the reaction, we submitted aryl bromide 8 to the reaction conditions (Scheme 4.2). Intramolecular cyclization to form 1-methylindane was observed in approximately 26% yield. The remaining mass balance was unreacted starting material and no uncyclized dehalogenated product was observed. These results are consistent with the formation of an aryl radical followed by rapid 5- exo cyclization onto the alkene. The reduced yield for the reaction is attributed to catalyst deactivation by the highly reactive primary alkyl radical formed upon cyclization. Similarly low yields and catalyst bleaching were observed in reductive dehalogenations of alkyl bromides (see

Appendix C).

Finally, making use of the potent reducing power of the acridyl radical excited states, reductive deoxygenation of aryl and benzylic alcohols has been demonstrated. Deoxygenation of alkyl and aryl alcohols is an important area and one that has been extensively studied.163

Nevertheless, the majority of methods for aryl C–O bond cleavage rely on transition metal catalysis often with the employment of expensive phosphine ligands and stoichiometric hydride sources. Liu and coworkers have recently demonstrated a mild, transition metal-free cleavage of aryl C–O bonds via single electron transfer (SET).164 The use of sodium iodide as a soft electron source in conjunction with 254nm UVC light allowed reduction and cleavage of aryl triflates to

62 the corresponding aryl radicals. We envisioned that upon photoexcitation of 1 with visible or

390nm light, deoxygenation of protected alcohols via a SET pathway might be possible.

To begin, 4-methoxyphenol was chosen as an electron rich test substrate and optimization of the protecting group on oxygen was performed (Table 4.3). Acetate, trifluoroacetate, and tosylate protecting groups resulted in no product formation under the standard dechlorination conditions. In particular, the trifluoroacetate group was fully deprotected during the course of the reaction and an adduct of this group with DIPEA was observed (ca. 40%) by 1H NMR and

GCMS. Reduction of 4-methoxyphenyl triflate yielded anisole in 26% with 53% concurrent deprotection to the phenol. Use of a methane sulfonate protecting group displayed moderate improvement to the yield as well as significantly reduced formation of 4-methoxyphenol.

Postulating that the mechanism of deprotection might involve nucleophilic cleavage of the O–S bond, we synthesized a camphor-derived sulfonate (entry 6) as a sterically hindered analogue.

However, upon submission to the reaction conditions, anisole was observed only in low yield with no improvement over deprotection. These results suggest that O–S bond cleavage does not occur by nucleophilic attack and instead likely proceeds via an electron transfer mechanism.

Extension of the substrate scope to a less electron rich aryl mesylate resulted in improved yield (Chart 4.2). Additionally, deoxygenation of a protected benzylic alcohol was also demonstrated in moderate yield. Further elaboration of this methodology for mild C–O bond cleavage of alkyl and aryl alcohols is ongoing.

Entrya R Group Yield of 10a (%)b Yield of 10b (%)b

1 0 25

2 0 quantitative

3 0 -

4 26 53

5 36 8

6 15 8

Table 4.3: Optimization of the protecting group for reductive deoxygenation of 9a. aConditions: All reactions were conducted in a 1 dram vial equipped with stir bar under air with 0.1 mmol substrate, 0.01mmol catalyst, 0.30mmol N,N-diisopropylethylamine (DIPEA) and 0.13ml acetonitrile. bYields determined by 1H NMR using 3.5μl hexamethyldisiloxane (HMDSO) as internal standard.

Chart 4.2: Initial extension of the reductive deoxygenation substrate scope.

4.3 Conclusions

In conclusion, we have examined the photophysical and catalytic properties of the stable acridyl radical (1) generated upon single electron reduction of acridinium 2. Photoexcitation of the higher energy absorption band of 1 results in Anti-Kasha’s rule emission and the population of two distinct emissive excited states. Spectral deconvolution of these states was performed and the state responsible for the high energy emission was tentatively assigned as a twisted intramolecular charge transfer (TICT) state. The excited state oxidation potentials of the D1 and

TICT states were estimated to be -2.91 V and -3.36 V vs. SCE respectively, making 1 the strongest visible light photoreductant yet reported. Evaluation of 1 as a photocatalyst in the benchmark reductive dehalogenation of aryl halides was performed. Electron rich, electron neutral, and electron poor aryl bromides and chlorides were all accessible in good yields under

390nm irradiation. Broad functional group tolerance was observed and application of this method for late stage modification of pharmaceutical scaffolds was realized. Additionally, deoxygenation of protected aryl and alkyl alcohols was demonstrated in moderate yields. Having established the highly reducing excited states accessible upon mild photoexcitation of the acridyl radical, we anticipate wide application of this catalyst scaffold in the development of new organic reaction methodology.

4.4 Future Work

Future work will consist of further characterization of the excited states of 1 so that assignment of each state may be fully supported. TD-DFT calculations and transient absorption measurements are currently ongoing. Additionally, comparison of 1 with a 9-tertbutyl acridyl radical incapable of undergoing the proposed intramolecular charge transfer is also in progress.

Further application of 1 in alkyl deoxygenations and other reductive transformations should be pursued.

4.5 Associated Content

Supporting information is available free of charge in Appendix C.

4.6 Acknowledgement

I would particularly like to thank M. Kyle Brennamen for his assistance in collection and interpretation of steady-state emission spectra. I could not have done any of this without his help.

This research made use of instrumentation (Edinburgh FLS920 Spectrometer) funded by the

UNC EFRC: Center for Solar Fuels, an Energy Frontier Research Center supported by the U.S.

Department of Energy, Office of Science, Office of Basic Energy Sciences (DESC0001011). The authors also thank Nick Tay for gracious donation of the substrate 5q.

APPENDIX A: SUPPORTING INFORMATION FOR “PROGRESS TOWARDS DEVELOPMENT OF SOLID-SUPPORTED ACRIDINIUM PHOTOCATALYSTS.”

A.1 General Reagents

FTO was purchased from Hartford Glass with a sheet resistance of 15 Ω/sq. Preparation of nanocrystalline ZrO2 or TiO2 over layers on a bare FTO glass has been described previously.165,166 Films of 4µm thickness, 1 cm2 geometric surface area on ca. 1 cm by 4 cm glass slides, were prepared using 10nm nanoparticles of ZrO2, 10-20nm nanoparticles of TiO2, or

<50nm nanoparticles of Al2O3.

A.2 Photostability Measurements

Photostability measurements were taken using a Cary50 UV-vis spectrophotometer.

Using a Teflon block, a catalyst loaded slide was positioned in a cuvette at a 45o angle to the beam path. The cuvette was equipped with an O-ring joint connecting to a glass top containing a

45o sidearm sealed by a Teflon valve. After adding solvent to the system, the O-ring and cap were attached and the system was sparged for 30 minutes using a small Argon line through the sidearm adapter. The system was then sealed and placed in the UV-vis. A 3W 450nm LED equipped with a focusing lens was positioned at 90o to the beam path. Careful alignment of the

UV-vis beam and the incident beam from the LED was performed to ensure irradiance and measurement of the same spot on the metal oxide thin film. After alignment, several spectra were collected in the absence of irradiation and then at sequential intervals (usually 3 or 5 minutes) during irradiation. Usually the system was first baselined against an unloaded metal oxide thin film. Alternatively, in some cases the system was baselined against the loaded slide and the

67 difference spectra collected. Reconstruction of the full spectral changes could be performed by addition of difference spectra to a spectrum of the initial loaded slide.

Figure A.1: Initial photostability measurements of 6a-TiO2 in acetonitrile. Scans are taken every 3 minutes over a period of 12 hours.

Figure A.2: Selected spectra for initial photostability measurements of 6a-Al2O3 in DCE.

Figure A.3: Photostability measurements of 6a-ZrO2 in deoxygenated DCM. Measurements collected every 5 minutes over a period of 4 hours.

Figure A.4: Photostability measurements of 6a-TiO2 in deoxygenated DCM. Measurements collected every 5 minutes over a period of 4 hours.

Figure A.5: Photostability of 6a-Al2O3 in the presence of 0.01mmol 16 in deoxygenated DCM. Spectra collected every 5 minutes for 345 minutes (5.75 hours).

Figure A.6: Selected spectra from photostability measurements of 8-ZrO2 in deoxygenated DCE.

Figure A.7: Selected spectra for photostability measurements of 6b-Al2O3 in deoxygenated DCM.

Figure A.8: Spectral changes upon irradiation of 9-mesityl-10-phenylacridinium tetrafluoroborate (50µM) in the presence of tetrabutylammonium hydroxide (2 eq.) in deoxygenated DCM. Excitation source: 3W 450nm LED. Spectra collected every 30 seconds for the first 10 minutes, every 90 seconds for the next 12 minutes, and every 5 minutes for the next 40 minutes.

Figure A.9: Selected spectra for photostability measurements of 19-TiO2 in deoxygenated DCM.

A.3 Fluorescence Measurements

An Edinburgh FLS920 Spectrometer was used for collection of time-resolved and steady state emission spectra. Time-resolved measurements were made using time correlated single photon counting (TCSPC) with a pulsed diode laser (444.2nm, typical pulse width of 95 ps).

Repetition rate was typically 10 MHz. Catalyst loaded slides were positioned at 45o to the incident beam and the detector in the O-ring equipped cuvette described above. Whenever a slide was used, a 430nm or 475nm long pass optical filter was employed to remove scattering of excitation wavelengths by the metal oxide.

Figure A.10: Emission spectrum of 6a (16µM) in deoxygenated DCM. Excitation at 450nm.

Figure A.11: Normalized absorption and emission of 6a-TiO2. Fluorescence was collected using excitation at 410nm with employment of a 430nm long pass filter.

Figure A.12: Normalized absorption and emission of 6a-ZrO2. Fluorescence was collected using excitation at 410nm with employment of a 430nm long pass filter.

Figure A.13: Normalized emission of 6b-ZrO2. Fluorescence was collected using excitation at 410nm with employment of a 430nm long pass filter.

Figure A.14: Normalized absorption and emission of 9-mesityl-10-methylacridinium tetrafluoroborate (12) in DCM. Excitation at 450nm.

Figure A.15: Lifetime decay traces for 6a in solution and at various loading times on TiO2. Excitation is at 444nm and emission is monitored at 515nm.

Figure A.16: Lifetime decay traces at 515nm for various surface anchored catalysts. Excitation at 444nm. Note that the decay for 19-TiO2 overlays with the decay trace for 23-TiO2.

Figure A.17: Steady-state fluorescence spectrum of A1-TiO2. Excitation with 444x diode laser.

Figure A.18: Lifetime decay trace at 515nm for A1-TiO2. Excitation with 444nm diode laser. Lifetime: 4.0ns.

A.4 Stern-Volmer Quenching Measurements

Stern-Volmer quenching experiments, both with catalyst in solution and with the anchored catalyst, were performed in argon saturated dichloromethane. Stern-Volmer analysis was conducted using the following equation:

τ 0 = 1 + K [Q] = 1 + k τ [Q] τ SV q 0 where 휏0 and 휏 are the lifetimes in the absence and presence of quencher respectively, 퐾푆푉 is the

Stern-Volmer quenching constant, 푘푞 is the bimolecular quenching constant, and [Q] is the concentration of quencher.

Figure A.19: Fluorescence lifetime of 6a (16µM) in deoxygenated DCM at the concentrations of 13 given.

Figure A.20: Stern-Volmer quenching analysis of the lifetime data reported in Figure A.18. The -1 Stern-Volmer quenching constant (KSV) is determined from the slope of the plot to be 51.5 M . From this value, the bimolecular quenching constant (kq) may be extracted using the relationship 9 -1 -1 KSV = kq휏0 to be 7.53x10 M s .

Figure A.21: Fluorescence lifetime of 6a-TiO2 in deoxygenated DCM at the concentrations of 13 given.

Figure A.22: Stern-Volmer quenching analysis of the lifetime data reported in Figure A.20. No clear Stern-Volmer quenching is observed.

Figure A.23: Fluorescence lifetime of 6a-TiO2 (low loading time) in deoxygenated DCM at the concentrations of 16 given. See Figure 2.4 in the main text for Stern-Volmer analysis.

A.5 Photophysics of anchored catalyst with applied electrochemical potential

A slide containing 6b-TiO2 was chosen and any exposed conductive FTO was covered with Kapton tape. The slide was placed in the O-ring cuvette in the Edinburgh FLS920

Spectrometer at a 45o angle to the incident laser beam as well as to the detector. A thin platinum mesh counter electrode was added on the non-conductive side of the slide opposite the metal oxide thin film. Electrolyte (0.1M tetrabutylammonium PF6) and reference electrode (Ag/AgCl) were added. An alligator clip was attached to the slide, ensuring contact with the conductive

FTO. Each of the electrodes (considering the slide to be the working electrode) were attached to a Pine Wavenow Potentiostat. Open circuit voltage was monitored initially to ensure proper contacts of the electrodes. Operating under chronoamperometry setting, the voltage was sequentially stepped in the positive direction. The current at each potential was monitored and lifetime measurements were collected only after the current was confirmed to have stabilized

(generally a wait time of 3-5 minutes). After measuring the lifetime of 6b-TiO2 at +2.2V, a potential of -300mV was applied and lifetime measurement taken to confirm reversibility of the

80 process. The final potential of +2.4V was then applied. Fluorescence lifetime measurement of the solution after completion of the experiment revealed only minor loss of the catalyst from the surface.

Figure A.24: Fluorescence lifetime of 6b-TiO2 at each applied potential.

A.6 Catalyst Synthesis

A.6.1 Synthesis of Catalyst 6.

Scheme A.1: Synthetic pathway to catalyst 6.

Preparation of N-allyl Acridone (3). To a large, flame-dried round bottom flask was added NaH (2.05g, 51.2mmol, 2.5eq) and approximately 200ml of dry DMF. Acridone 2 (4g,

20.5mmol, 1eq) was added to this and the solution was stirred at room temperature for 30min.

Then, allylbromide (5.3 ml, 61.5mmol, 3eq) was added and the solution was stirred overnight at room temperature. The reaction mixture was quenched carefully with water and then poured into ice-water. The resulting precipitate was filtered. washed with water and hexanes, and then dried

1 in a vacuum oven to yield 3.01g (62%) of a pale yellow solid. H NMR (400MHz, CDCl3) δ

8.60 (dd J = 8.0 Hz, J = 4.0 Hz, 2H), 7.72 (dt J = 8.0 Hz, J = 1.6Hz, 2H), 7.44 (d J = 8.6Hz,

2H), 7.32 (dt J = 7.5Hz, J = 0.7Hz, 2H), 6.17 (m, 1H), 5.35 (d J = 10.6Hz, 1H), 5.14 (d J =

13 17.2Hz, 1H), 5.00 (m, 2H) ppm. C NMR (600MHz, CDCl3) δ 178.2, 142.2, 133.9, 130.5,

127.7, 122.5, 121.5, 117.5, 115.1, 49.3 ppm.

Preparation of (5). N-allyl Acridone (3) (2.99g, 12.8mmol, 1eq), H2PtCl6 (~5mg), and approximately 130ml of dry DCM were combined in a large round bottom flask. Trichlorosilane

(3.9ml, 38.3mmol, 3eq) was added and the reaction mixture heated at 30 oC. After 4hrs the reaction was believed to be complete by 1H NMR (unfortunately the presence of significant amounts of DCM shifts the starting material alkene peaks and hides them). Pyridine (10.4ml,

128mmol, 10eq) and 2-propanol (9.8ml, 128mmol, 10eq) were added. The reaction mixture was

82 filtered, and the filtrate was washed with water and aqueous bicarbonate. The organic layer was separated and the solvent removed in vacuo to leave 3g of a yellow solid that was found by 1H

NMR to still contain approximately 40% starting acridone. The product was separated by column chromatography (20% ethyl acetate:hexanes) to yield 1.87g (33%) of a pale yellow solid. 1H

NMR (400MHz, CDCl3) δ 8.62 (dd J = 8.0Hz, J = 1.6Hz, 2H), 7.75 (dt J = 7.6Hz, J = 1.6Hz,

2H), 7.64 (d J = 8.8Hz, 2H), 7.32 (t J = 7.6Hz, 2H), 4.42 (m, 2H), 4.31 (sept, J = 6.4Hz, 3H),

2.10 (m, 2H), 1.26 (d J = 6.0Hz, 18H), 0.84 (t J = 7.6Hz, 2H) ppm. 13C NMR (600MHz,

CDCl3) δ 178.1, 141.9, 133.8, 127.9, 122.4, 121.1, 114.9, 65.3, 48.2, 25.7, 20.8, 8.9 ppm.

Preparation of 6a and 6b. Acridone 3 (1.5g, 3.4mmol, 1eq) and THF (17ml) were added to a flame dried round bottom flask with stir bar. Mesityl magnesiumbromide (17.2ml,

17.2mmol, 5eq) was added and the solution was stirred for at room temperature. After 21 hours,

TLC analysis showed significant starting material remaining. The reaction was heated at 40 oC for approximately 11 hours at which point TLC indicated high conversion. The reaction was quenched with water, extracted with ethyl acetate, and the organic layer dried with sodium sulfate. Removal of the solvent in vacuo yielded a dark oily material which was purified by column chromatography (10% MeOH/DCM). The isolated material was recrystallized from acetone/hexanes to yield 429mg (22.5%) of a yellow golden material (6a). 1H NMR (400 MHz,

CDCl3) δ 9.11 (d, J = 9.3 Hz, 2H), 8.45 (ddd, J = 9.3, 6.4, 1.9 Hz, 2H), 7.87 – 7.75 (m, 4H), 7.15

(s, 2H), 5.87 – 5.77 (m, 2H), 4.33 (hept, J = 6.1 Hz, 3H), 2.47 (s, 3H), 2.45 – 2.37 (m, 2H), 1.72

13 (s, 6H), 1.28 – 1.17 (m, 20H) ppm. C NMR (151 MHz, CDCl3) δ 162.7, 140.6, 140.4, 139.7,

135.7, 129.3, 129.1, 129.1, 128.6, 125.9, 119.7, 65.5, 53.3, 25.7, 23.4, 21.3, 20.2, 8.8 ppm. IR signals of note: 3406 cm-1 (broad), 3479 cm-1 (broad).

Ion exchange of 6a to 6b was performed by dissolving 6a and excess sodium perchlorate in acetone. This solution was cooled in the fridge, filtered, and the filtrate was diluted with dichloromethane. The resulting solution was washed twice with water, dried with sodium sulfate, and the solvent removed in vacuo. The residual solid was redissolved in acetone, precipitated

1 with addition of hexane/pentanes, and collected as a yellow solid. H NMR (400 MHz, CDCl3) δ

8.83 (d, J = 9.3 Hz, 2 H), 8.43 (t, J = 7.8 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.83 – 7.75 (m, 2H),

7.18 (s, 2H), 5.64 – 5.52 (m, 2H), 4.37 (hept, J = 6.0 Hz, 3H), 2.50 (s, 3H), 2.45 (t, J = 8.6 Hz,

2H), 1.76 (s, 6H), 1.29 (d, J = 6.2 Hz, 18H), 1.15 (t, J = 7.3 Hz, 2H). IR signals of note: no defined peak above 3000 cm-1, large perchlorate signal at 1079 cm-1.

A.6.2 Synthesis of Acridinium 8.

Scheme A.2: Synthesis of catalyst 8.

Preparation of (9). Allyl magnesium bromide (24.0ml, 24.0mmol, 1.5eq was cooled to 0 oC and 4-Bromobenzylbromide (4g, 16.0mmol, 1eq) was added. The solution was stirred at room temperature overnight and then quenched (carefully) with water. The solution was extracted with ethyl acetate and the organic layer dried with Na2SO4. The solvent was removed in vacuo to yield approximately 3.17g (87%) of a volatile clear oil which was considered clean enough to carry

1 forward. H NMR (400MHz, CDCl3) δ 7.40 (d J = 8.0Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 5.91 –

5.73 (m, 1H), 5.11 – 4.92 (m, 2H), 2.67 (t, J = 7.7 Hz, 2H), 2.35 (q, J = 7.4 Hz, 2H) ppm. 13C

NMR (151 MHz, CDCl3) δ 140.8, 137.6, 131.3, 130.2, 119.5, 115.3, 35.3, 34.8 ppm.

Preparation of (10). Acridone (1.0g, 5.1mmol, 1.0eq), 9 (1.3g, 6.1mmol, 1.2eq), and

K2CO3 (1.42g, 10.2mmol, 2.0eq) were combined in a 100ml 2-neck round bottom flask equipped with a stir bar and reflux condenser (air cooled). 2,2,6,6-tetramethyl-3,5-heptanedione (214μl,

1.0mmol, 0.2eq) and DMF (25ml) were added. The solution was briefly sparged with nitrogen and then copper iodide (98mg, 0.05mmol, 0.1eq) was added. The solution was sparged again with nitrogen for 20 minutes, sealed, and heated to reflux for 3 days. The reaction was removed

85 from the heat, partitioned between aqueous sodium bicarbonate and DCM, and extracted with

DCM. The organic layer was dried with Na2SO4 and the majority of the solvent removed in vacuo. The product was found to crystallize from the remaining DMF. The solution was placed in the fridge to aid crystallization and then the crystals were collected by filtration to give 627mg

1 (38%) of a pale brown solid. H NMR (400MHz, CDCl3) δ 8.58 (dd, J = 8.0, 1.6 Hz, 2H), 7.65 –

7.39 (m, 4H), 7.31 – 7.23 (m, 4H), 6.78 (d, J = 8.5 Hz, 2H), 5.94 (ddt, J = 16.9, 10.2, 6.6 Hz,

1H), 5.13 (dd, J = 17.1, 1.7 Hz, 1H), 5.07 (dd, J = 10.2, 1.5 Hz, 1H), 2.93 – 2.85 (m, 2H), 2.52

13 (dt, J = 7.8, 6.5 Hz, 2H) ppm. C NMR (151 MHz, CDCl3) δ 178.2, 143.6, 143.3, 137.5, 136.6,

133.2, 131.1, 129.8, 127.3, 121.8, 121.5, 116.9, 115.6, 35.4, 35.1 ppm.

Preparation of (11). Compound 10 (604mg, 1.9mmol, 1.0 eq.), trichlorosilane (0.28ml,

2.8mmol, 1.5 eq.), dichloromethane (ca. 20 ml), and Karstedt’s catalyst (100µl, 2% Pt solution in xylenes) were combined in a round bottom flask with stir bar and let stir at room temperature for

2 days. TLC analysis showed full conversion. Solvent was removed in vacuo and residue was redissolved in DCM. Pyridine (0.6ml, 7.4mmol, 4 eq.) and isopropanol (0.6ml, 7.4mmol, 4 eq.) were added and stirred overnight. The resulting solution was washed twice with water, dried with sodium sulfate, and the solvent removed to leave 0.85g (86%) of a yellow solid. 1H NMR (400

MHz, CDCl3) δ 8.61 (d, J = 8.1 Hz, 2H), 7.55 – 7.49 (m, 4H), 7.32 – 7.25 (m, 4H), 6.81 (d, J =

8.6 Hz, 2H), 4.26 (h, J = 4.8 Hz, 3H), 2.82 (t, J = 7.4 Hz, 2H), 1.83 (m, 3H), 1.57 (m, 2H), 0.76 –

0.66 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3) δ 178.2, 144.6, 143.3, 136.3, 133.2, 131.0,

129.6, 127.3, 121.8, 121.5, 116.9, 64.9, 35.4, 34.8, 25.6, 22.7, 12.0.

Preparation of (9). Compound 11 (0.44g, 0.83mmol, 1eq) was added to a 25ml round bottom flask with stir bar. Mesityl magnesiumbromide (2.5ml, 2.5mmol, 1M in THF, 3eq) was added and the reaction was heated at 45 oC for three days. The solvent has mostly evaporated so some ether was added followed by water and a little bit of ethanol. Brine was added and the mixture was extracted with ethyl acetate, the organics dried with Na2SO4, and the remaining solution concentrated by blowing nitrogen over it. The residue was redissolved in acetone hexanes were added, and the material was placed in the fridge for a little bit. A small amount

(44mg) of an orange precipitate was collected but was found to be impure. A bright yellow precipitate formed overnight, and 168mg (31%) was collected by filtration and found to be pure

1 1 by H NMR. H NMR (400MHz, CDCl3) δ 8.24 – 8.19 (m, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.86 –

7.82 (m, 2H), 7.79 – 7.71 (m, 4H), 7.67 (d, J = 9.1 Hz, 2H), 7.18 (s, 2H), 4.25 (hept, J = 6.1 Hz,

3H), 2.93 – 2.84 (m, 2H), 2.50 (s, 3H), 1.90 – 1.81 (m, 8H), 1.32 – 1.14 (m, 20H), 0.75 – 0.67

13 (m, 2H) ppm. C NMR (151 MHz, CDCl3) δ 164.5, 147.5, 142.1, 140.5, 139.1, 136.1, 134.2,

131.6, 129.1, 128.8, 128.8, 127.8, 126.0, 120.4, 64.9, 35.6, 34.8, 25.7, 23.0, 21.3, 20.6, 12.0 ppm.

A.6.3 Synthesis of Acridinium 19.

Scheme A.3: Synthesis of catalyst 19.

Preparation of (20). To a large round bottom flask with stir bar, added sodium hydride

(1.07g, 60% in mineral oil, 26.6mmol, 1.3 eq.) and DMF (ca. 200ml). Added acridone 12 (4g,

20.5mmol, 1.0 eq.) portionwise carefully (effervescence of hydrogen observed upon addition).

Stirred fluorescent green solution at room temperature for 10 minutes after which an additional portion of sodium hydride was added (0.78g, 19.4mmol, 0.95 eq.). The solution was stirred at room temperature for 50 minutes and then 11-Bromo-1-undecene (6.2g, 26.6mmol, 1.3 eq.) was added. The resulting solution was stirred at room temperature for four days while monitoring by

TLC. After this time, the solution was quenched carefully with water and partitioned between

DCM and water. The organic layer was dried with sodium sulfate and most solvent removed in vacuo. The resulting material was mostly purified by column chromatography (20%

EtAc/hexanes) to leave 3.85g of a crude yellow solid. A second column generated pure material.

1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 7.8 Hz, 2H), 7.53 (d, J = 8.7

Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 5.97 – 5.72 (m, 1H), 5.02 (d, J = 16.9 Hz, 1H), 4.96 (d, J = 9.9

Hz, 1H), 4.37 (t, J = 8.3 Hz, 2H), 2.07 (p, J = 7.1 Hz, 2H), 1.97 (p, J = 8.1 Hz, 2H), 1.59 (p, J =

13 7.4 Hz, 2H), 1.38 (m, 18H) ppm. C NMR (151 MHz, CDCl3) δ 178.0, 141.8, 139.2, 133.9,

128.0, 122.5, 121.2, 114.6, 114.2, 46.3, 33.8, 29.6, 29.4, 29.4, 29.1, 28.9, 27.2, 27.0 ppm.

Preparation of (21). Compound 20 (0.61g, 1.8mmol, 1.0 eq.) was combined in a round bottom flask with trichlorosilane (0.27ml, 2.6mmol, 1.5 eq.), Karstedt’s catalyst (100µl, 2% Pt in xylenes) and THF (ca. 20ml). The solution was stirred at room temperature for 2 days after which time an aliquot indicated full conversion by proton NMR. The solvent was removed in vacuo, the residue redissolved in DCM and pyridine (0.6ml) and isopropanol (0.6ml) were added and the solution stirred for another day. The solution was washed twice with water and the organic layer dried with sodium sulfate and the solvent removed to leave 0.92g (95%) of an oily

1 solid. H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 7.8 Hz, 2H), 7.53 (d, J

= 8.7 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 4.37 (t, J = 8.4 Hz, 2H), 4.23 (hept, J = 6.0 Hz, 3H), 1.97

(t, J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.34 – 1.18 (m, 19H), 0.64 – 0.56 (m, 2H) ppm. 13C NMR (151

MHz, CDCl3) δ 178.0, 141.8, 133.9, 128.0, 122.5, 121.2, 114.6, 64.8, 46.3, 33.3, 29.6, 29.6,

29.6, 27.2, 26.5, 25.6, 25.3, 23.0, 12.0 ppm.

Preparation of catalyst (19). To a found bottom flask with stir bar was added compound

21 (0.44g, 0.749mmol, 1.0 eq.), THF (3ml), and mesityl magnesium bromide (1M, 2.4ml,

2.4mmol, 3.0 eq.). The solution was stirred at room temperature for 3 days after which is was quenched with water. Brine and ethyl acetate were added and the solution was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and the solvent evaporated. The material was taken up in acetone, hexanes were added, and the solution was placed in the freezer.

A yellow solid precipitated, but was mostly insoluble in chloroform. As clean isolation of the product was challenging, the mother liquor was acidified with trifluoroacetic acid and used as a loading solution directly.

Figure A.25: Normalized absorption and emission of 19-TiO2. The dotted line is extrapolation of the emission to determine E0,0.

A.6.4 Synthesis of Acridinium 22.

Scheme A.4: Synthesis of catalyst 22.

Preparation of compound (a22). To a round bottom flask equipped with a reflux condenser, acridone 2 (400mg, 2.0mmol, 1.0 eq.) was added. Copper iodide (39mg, 0.2mmol,

0.1 eq.), 4,4’-biphenyl (1.9g, 6.1mmol, 3.0 eq.), potassium carbonate (566mg, 4.1mmol, 2.0 eq.),

2,2,6,6-tetramethyl-3,5-heptanedione (0.43ml, 0.4mmol, 0.2 eq.), and DMF (12ml) were added.

The system was sparged thoroughly with nitrogen, sealed, and heated to 150 oC for 4 days. After cooling, the solution was acidified with 3N HCl and a yellow precipitate formed which was collected by filtration. Purification by column chromatography was performed (20%

EtAc/hexanes) followed by recrystallization from ethyl acetate to yield 350mg (40%) of a yellow

1 solid. H NMR (600 MHz, CDCl3) δ 8.63 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.69 (d, J

= 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 8.6 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.33 (t,

13 J = 7.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H) ppm. C NMR (151 MHz, CDCl3) δ 178.2, 143.1,

141.4, 138.6, 138.4, 133.4, 132.3, 130.6, 129.5, 128.8, 127.4, 122.6, 121.9, 121.7, 116.8 ppm.

Preparation of compound (b22). To a solution of a22 (160mg, 0.38mmol, 1.0 eq.) in

THF (10ml), was added mesityl magnesium bromide (1M, 1.1ml, 1.1mmol, 3.0 eq.). The solution quickly became a dark red color. The solution was stirred at 55 oC for 2 days after which time TLC confirmed full conversion. The solution was quenched with saturated aqueous sodium bicarbonate, extracted with DCM, washed with brine and saturated aqueous bicarbonate, dried with sodium sulfate, and the solvent removed in vacuo. The resulting material was dissolved in ether and filtered to collect 52mg (25%) of the alcohol product. The filtrate was acidified with

1 HBF4 and filtered again to collect 136mg (59%) of a bright yellow solid. H NMR (600 MHz,

CDCl3) δ 8.17 (ddd, J = 9.1, 6.7, 1.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.99 – 7.94 (m, 2H), 7.91

(d, J = 8.4 Hz, 2H), 7.80 (ddd, J = 8.7, 6.7, 0.9 Hz, 2H), 7.76 (d, J = 9.1 Hz, 2H), 7.72 (d, J = 8.5

Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.21 (s, 2H), 2.52 (s, 3H), 1.90 (s, 6H) ppm. 13C NMR (151

MHz, CDCl3) δ 164.7, 143.6, 142.1, 140.4, 138.8, 137.9, 136.3, 136.1, 132.4, 129.9, 129.3,

129.0, 128.9, 128.8, 128.4, 126.1, 123.2, 120.3, 65.9, 20.2 ppm.

Preparation of catalyst 22. To a round bottom flask containing b22 (40mg, 0.06mmol,

1.0 eq.) and tetrabutylammonium iodide (31mg, 0.08, 1.3 eq.) was added in a glovebox bis(acetonitrile)-(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (3.5mg, 0.009mmol, 0.14 eq.), triethoxysilane (60µl, 0.32mmol, 5.0 eq.), triethylamine (50µl, 0.36mmol, 5.5 eq.), and DMF

(0.5ml). The system was sealed, brought out of the glovebox, and heated at 80 oC for 3 hours.

The solution was added carefully to ether and cooled in the fridge. The resulting solid was carefully collected and rinsed with ether. 1H NMR and LCMS show only 10-15% product in the mixture. Methods for separation of 22 from b22 were unclear, especially given the possible sensitivity of the silane to hydrolysis. Therefore, a loading solution of this material was made directly.

Figure A.26: Absorption spectrum of 22-TiO2.

A.6.5 Synthesis of Acridinium 23.

Scheme A.5: Synthesis of catalyst 23.

Preparation of compound (a23). To a round bottom flask was added acridone 3 (1.0g,

4.25mmol, 1.0 eq.), diisopropylchlorosilane (1.09ml, 6.38mmol, 1.5 eq.), and THF (ca. 45ml).

To this, Karstedt’s catalyst (100µl, 2% Pt in xylenes) was added and the reaction stirred for several days. 1H NMR of an aliquot showed low conversion after 5 days. Additional portions of

94 diisopropylchlorosilane and Karstedt’s catalyst were added and the system was heated under reflux for 4 hours after which time high conversion was observed. The solvent was removed in vacuo, the residue redissolved in DCM and pyridine and isopropanol (1.5 eq. each) were added and stirred for several hours. The solution was then partitioned between DCM and saturated aqueous bicarbonate, the organic layer was dried with sodium sulfate, and the solvent removed.

Purification by column chromatography (gradient 100% hexanes to 100% ethyl acetate) was

1 performed to yield 0.61g (35%) of pure solid material. H NMR (500 MHz, CDCl3) δ 8.62 (dd, J

= 8.1, 1.7 Hz, 2H), 7.76 (ddd, J = 8.7, 6.9, 1.8 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.33 (ddd, J =

7.9, 6.9, 0.8 Hz, 2H), 4.46 – 4.27 (m, 2H), 4.13 (hept, J = 6.0 Hz, 1H), 2.21 – 1.99 (m, 2H), 1.22

(d, J = 6.0 Hz, 6H), 1.12 – 1.04 (m, 14H), 0.90 – 0.82 (m, 2H) ppm.

Preparation of catalyst 23. To a round bottom flask was added a23 (0.6g, 1.4mmol, 1.0 eq.) and THF (10ml). The solution was sparged thoroughly with argon and then mesityl magnesium bromide (1M, 3.5ml, 3.5mmol, 2.5 eq.) was added. The solution was heated to 50 oC for one day, cooled and worked up between DCM and saturated aqueous sodium bicarbonate.

The organic layer was dried with sodium sulfate and the solvent removed. The residue was purified by column chromatography (gradient 100% DCM to 10% methanol/DCM). The material was then dissolved in acetone with excess sodium perchlorate, stirred, then washed with water and extracted with DCM. Drying of the organic layer and removal of the solvent gave 81mg

(9%) of a yellow solid. 1H NMR (600 MHz, Chloroform-d) δ 8.68 (d, J = 9.3 Hz, 2H), 8.46 –

8.34 (m, 2H), 7.86 (dd, J = 8.6, 1.4 Hz, 2H), 7.80 (dd, J = 8.4, 6.8 Hz, 2H), 7.15 (s, 2H), 5.65 –

5.29 (m, 2H), 4.14 (hept, J = 6.0 Hz, 1H), 2.47 (s, 3H), 2.36 (p, J = 8.3 Hz, 2H), 1.72 (s, 6H),

13 1.19 (d, J = 6.0 Hz, 6H), 1.08 – 1.00 (m, 18H) ppm. C NMR (151 MHz, CDCl3) δ 162.9,

140.7, 140.4, 139.5, 129.3, 129.1, 128.5, 126.1, 118.9, 65.5, 53.7, 47.5, 26.2, 23.9, 21.3, 20.1,

-1 17.8, 17.7, 12.9, 9.1, 7.8 ppm. IR: peaks of note 1077 cm (ClO4).

A.6.6 Synthesis of Acridinium 24.

Scheme A.6: Synthesis of catalyst 24.

Preparation of compound (a24). To a round bottom flask was added acridone 2 (1.51g,

7.8mmol, 1.1 eq.), copper (I) iodide (134mg, 0.7mmol, 0.1 eq.), and potassium carbonate (1.95g,

14.1mmol, 2.0 eq.). In a nitrogen filled glovebox, added silyl protected 4-bromobenzyl alcohol

(3g, 7.1mmol, 1.0 eq.), 2,2,6,6-tetramethyl-3,5-heptanedione (294µl, 1.4mmol, 0.2 eq.), and

DMF (8ml). The system was sealed, removed from the glovebox, and heated to 120 oC for 2

96 days. The solution was then diluted with DCM, washed with saturated aqueous sodium bicarbonate and with brine, the organic layer was dried with sodium sulfate and the solvent removed. The residual material was purified by column chromatography (50% EtAc/hexanes) and further purified by washing with hexanes to give product as an off-white powder (1.28g,

1 34%). H NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 8.1, 1.6 Hz, 2H), 7.79 (dd, J = 7.9, 1.6 Hz,

4H), 7.69 (d, J = 8.2 Hz, 2H), 7.57 – 7.43 (m, 9H), 7.37 – 7.30 (m, 3H), 6.98 – 6.59 (m, 2H),

4.98 (s, 2H), 1.20 (s, 9H) ppm.

Preparation of compound (b24). To a dry, 2-neck round bottom flask, added THF

(12ml). Cooled to -78 oC and added t-butyllithium (1.7M, 3.6ml, 6.2mmol, 2.6 eq.). This was followed by dropwise addition of 2-bromomesitylene (0.47ml, 3.1mmol, 1.3 eq.). The solution was stirred at -78 oC for 30 minutes after which time a24 (1.28g, 2.4mmol, 1.0 eq.) was added in one portion. The solution was allowed to slowly warm to room temperature overnight. The solution was then carefully quenched with water, diluted with DCM and saturated aqueous sodium bicarbonate. The organic layer was separated and the solvent removed in vacuo. The residue was dissolved in ether and filtered. Addition of HBF4 in ether resulted in precipitation of a fine yellow solid. 1H NMR confirmed the product structure still containing the silyl protecting group. Dissolving the material in DCM and stirring with HBF4 overnight resulted in clean

97 deprotection of the silyl group to give 436mg (37%) of a fine yellow solid. 1H NMR (600 MHz,

CDCl3) δ 8.24 – 8.16 (m, 2H), 8.00 – 7.92 (m, 4H), 7.81 (m, 4H), 7.67 (d, J = 8.3 Hz, 2H), 7.21

13 (s, 2H), 5.00 (s, 2H), 2.52 (s, 3H), 1.86 (s, 6H) ppm. C NMR (151 MHz, CDCl3) δ 164.4,

146.1, 142.0, 140.5, 139.1, 136.0, 135.2, 130.0, 129.2, 129.1, 128.7, 128.6, 127.6, 125.8, 120.6,

64.1, 21.3, 20.2 ppm.

Preparation of catalyst (24). Trifluoroacetic acid (2ml) and b24 (212mg, 0.4mmol, 1.0 eq.) were combined in a round bottom flask under a balloon of oxygen. This solution was cooled to 0 oC and sodium nitrite (119mg, 1.7mmolm 4 eq.) was added in one portion. The solution was stirred at 0 oC for 20-30 minutes and then let warm to room temperature. After 6 hours, the solution was diluted with water and extracted with DCM. The organic layer was dried with sodium sulfate and the solvent removed in vacuo. NMR of the solid showed a mixture of acid and aldehyde. The material was dissolved in acetone and a solid precipitated by addition into ether. The solid, confirmed to be only the aldehyde product, was filtered off and the solvent removed from the liquor. Redissolving this material in acetonitrile, it was used directly to load onto metal oxides.

A.6.7 Synthesis of Acridinium 25.

Scheme A.7: Synthesis of catalyst 25.

Preparation of compound (a25). To a round bottom flask with a reflux condenser was added 9-mesitylacridine (50mg, 0.17mmol, 1.0 eq) and methyl 4-(iodomethyl)benzoate (150mg,

0.54mmol, 3.2 eq.), and acetonitrile (5-10ml). This solution was heated to reflux for 3 days.

Stirring the residue with ether followed by decanting led to clean solid product (96mg, 99%). 1H

NMR (400 MHz, CDCl3) δ 8.40 (d, J = 7.6 Hz, 4H), 8.13 (d, J = 8.1 Hz, 2H), 8.05 – 7.97 (m,

2H), 7.94 – 7.82 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.22 (s, 2H), 6.97 (s, 2H), 3.95 (s, 3H), 2.53

(s, 3H), 1.89 (s, 6H).

Preparation of catalyst (25). In a 1 dram vial with stir bar was added a25 (50mg,

0.09mmol, 1.0 eq.), phenyltrimethylsilane (125µl, 0.73mmol, 8.1 eq.), and iodine (192mg,

0.76mmol, 8.4 eq.). The vial was sealed with a septum, placed under positive nitrogen pressure and heated to 110 oC for 2 hours. After cooling, added DCM and water and extracted with DCM.

Dried organic layer and removed solvent to leave a purple solid. Washed with ether, then washed with aqueous KPF6. Stirred in DCM/KPF6 (aq) mixture, separated organic layer, dried with sodium sulfate and removed solvent. Repeated washing with ether, then stirred in acetone/DCM

1 with KPF6, washed with water and isolated solid material. H NMR (400 MHz CDCl3) δ 8.39 (d,

J = 9.1 Hz, 2H), 8.31 (t, J = 8.0 Hz, 2H), 8.10 (d, J = 8.1 Hz, 2H), 7.95 (dd, J = 8.7, 1.4 Hz, 2H),

7.81 (dd, J = 8.8, 6.6 Hz, 2H), 7.20 (s, 2H), 6.80 (s, 2H), 2.51 (s, 3H), 1.81 (s, 6H) ppm. 19F

31 NMR (376 MHz, CDCl3) δ -73.19 (d, J = 713.0 Hz) ppm. P NMR (162 MHz, CDCl3) δ -

144.68 (hept, J = 713 Hz).

A.6.8 Synthesis of Acridinium A1.

Scheme A.8: Synthesis of catalyst A1.

100

Preparation of compound (aA1). To a round bottom flask was added sodium hydride

(163mg, 60% in mineral oil, 4.2mmol, 2.5 eq.). This was washed several times with hexanes.

Then di-tertbutyl acridone (530mg, 1.7mmol, 1.0 eq.) and THF (22ml) were added. The solution was stirred at room temperature for 30 minutes. Then allyl bromide (0.42ml, 4.9mmol, 2.8 eq.) was added and the solution stirred at room temperature for 1 day. Full conversion was confirmed by TLC. The solution was poured into ice water, whereupon a precipitate formed. Filtration and

1 collection of this material yielded a clean solid (367mg, 65%). H NMR (400 MHz, CDCl3) δ

8.50 (d, J = 8.4 Hz, 2H), 7.48 – 7.32 (m, 4H), 6.22 (ddt, J = 17.5, 10.6, 4.1 Hz, 1H), 5.40 (d, J =

10.6 Hz, 1H), 5.25 (d, J = 17.3 Hz, 1H), 5.07 – 4.92 (m, 2H), 1.43 (s, 18H) ppm.

Preparation of compound (bA1). To a round bottom flask was added aA1 (367mg,

1.1mmol, 1.0 eq.), trichlorosilane (0.32ml, 3.2mmol, 3.0 eq.), hydrogen hexachloroplatinate

(2mg), and DCM (11ml). The solution was heated at 30 oC for 1 day. The reaction was quenched with addition of pyridine (0.85ml, 10.6mmol, 10 eq.) and isopropanol (0.81ml, 10.6mmol, 10 eq.). The solution was washed with water and saturated aqueous sodium bicarbonate, the organic layer was dried with sodium sulfate, and the solvent removed. This residue was redissolved in

101 acetone, the solvent removed in vacuo and the material placed under vacuum at 70 oC to leave an

1 viscous oil (0.59g, quant.). H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 2H), 7.48 (d, J =

1.6 Hz, 2H), 7.38 (dd, J = 8.5, 1.5 Hz, 2H), 4.40 – 4.33 (m, 2H), 4.33 – 4.21 (m, 3H), 2.11 (td, J

= 11.9, 10.1, 5.5 Hz, 2H), 1.46 (s, 18H), 1.22 (d, J = 6.1 Hz, 18H), 0.88 – 0.81 (m, 2H).

Preparation of catalyst A1. To a round bottom flask was added bA1 (0.59g, 1.1mmol,

1.0 eq.), THF (11ml), and mesityl magnesium bromide (1M, 3.2ml, 3.2mmol, 3.0 eq.). The solution was heated at 40 oC for 4 days. The reaction was quenched with water, partitioned between DCM and aqueous sodium bicarbonate, and extracted with DCM. The solvent was removed and the residue purified by column chromatography (10% MeOH/DCM). The material was redissolved in acetone and precipitated by addition of hexanes and cooling. The liquor was then decanted and the solid washed twice with hexanes and dried to give 50mg of a yellow solid

(7%). 1H NMR (600 MHz, Chloroform-d) δ 8.46 (d, J = 1.5 Hz, 2H), 7.81 (dd, J = 9.1, 1.4 Hz,

2H), 7.74 (d, J = 9.0 Hz, 2H), 7.16 (s, 2H), 5.91 (t, J = 8.2 Hz, 2H), 4.27 (hept, J = 6.1 Hz, 3H),

2.50 (s, 3H), 2.42 – 2.35 (m, 2H), 1.77 (s, 6H), 1.58 (s, 18H), 1.20 (d, J = 6.1 Hz, 18H), 1.12 –

13 1.07 (m, 2H) ppm. C NMR (151 MHz, CDCl3) δ 163.6, 160.3, 140.9, 140.1, 129.5, 128.9,

128.6, 127.2, 124.1, 114.1, 65.3, 53.7, 37.1, 30.7, 25.6, 23.3, 21.3, 20.3, 10.0 ppm.

102

A.7 Reactions with the surface-anchored catalysts

A.7.1 General reaction details.

Substrate and a small stir bar were added to an unjointed (not screw-cap) 1-dram vial.

This was brought into a nitrogen filled glovebox and solvent added. The top glass portion of a catalyst-loaded slide was carefully trimmed to be able to fit snugly inside a small septum. The vial containing substrate solution was then capped with this septum. The slide was suspended by the septum such that the metal oxide thin film was held in solution above the stir bar. The vial was sealed with electrical tape, removed from the glovebox, and placed on a stir plate in front of

450nm LEDs for the allotted reaction time. Alternatively, this reaction setup was assembled outside the glovebox and carefully sparged with nitrogen for 10-20 minutes prior to irradiation.

After completion of the reaction, the slide was removed and rinsed with solvent. The solvent was

1 then removed and the residue redissolved in CDCl3 for analysis by H NMR.

A.7.2 Specific reactions

Solution phase reaction: In an NMR tube, added CDCl3 (1.5ml), trans-anethole (150µl),

2,6-lutidine (30µl), thiophenol (21µl), acetic acid (570µl) and acridinol (precursor of 6a isolated after Grignard addition). Sparged solution with nitrogen for 10 minutes. Aquired 1H NMR and then placed in front of 450nm LEDs for 14 hours. After which time, observed full conversion to product by 1H NMR.

Reaction with 6a-ZrO2: Followed general procedure outlined in section A.7.1 with the same reagents as in the solution phase reaction. Irradiated for 48 hours, but observed no product

103 formation. The reaction was repeated with sodium benzene sulfinate as the hydrogen atom donor, but no product formation was observed after 17 hours of irradiation.

Conversion of 16 with 6a-ZrO2: Followed general procedure outlined in section A.7.1. In a 1 dram vial in the glovebox were combined 16 (2.5mg, 0.01mmol), 6a-ZrO2, and CDCl3

(3ml). After irradiation with 450nm LEDs for 16 hours, 82% conversion to product was observed by 1H NMR.

Conversion of 16 with 6a-TiO2: Followed general procedure outlined in section A.7.1. In a 1 dram vial in the glovebox were combined 16 (5.0mg, 0.02mmol), 6a-ZrO2, and DCM (3ml).

The reaction was monitored by GCMS and full conversion to product was obserbed in 60 minutes.

Figure A.27: GCMS conversion trace for rearrangement of 16 catalyzed by 6a-TiO2.

104

Solution phase conversion of substrates by 12: Substrate (0.01mmol), 12 (0.0001mmol as a solution in CDCl3), and CDCl3 (1.5ml) were combined in a 1 dram vial. The solution was sparged with nitrogen and then irradiated with 450nm LEDs for 60 minutes. 1H NMR confirmed quantitative conversion of each substrate to product with hexamethyldisiloxane (HMDSO) as internal standard.

Conversion of 16 with 19-TiO2: Followed general procedure outlined in section A.7.1. In a 1 dram vial were combined 16 (3.8mg), 19-ZrO2, and DCM (3ml). After sparging with nitrogen, the sample was irradiated for several hours (3-5 hours) with 450nm LEDs. After

1 removal of the solvent and redissolving the residue in CDCl3, the conversion by H NMR was only found to be ca. 60%.

105

Conversion of 16 with A1-TiO2: Followed general procedure outlined in section A.7.1.

In a 1 dram vial were combined 16 (5.0mg, 0.02mmol), A1-TiO2, and CDCl3 (3ml). The solution was sparged with nitrogen and then the system was irradiation with 450nm LEDs for 60 minutes.

1H NMR shows only 15% conversion to product.

A.8 Recycling attempts with surface-anchored catalysts.

Reactions were setup as detailed in section A.7.1. Three cycles of 60 minute irradiation time were performed using catalyst 6a-TiO2. After each cycles, the slide was removed, rinsed thoroughly with solvent, and then prepared for the next cycle. All reactions were setup outside the glovebox with careful sparging of nitrogen. Recycling was also attempted with 6b-TiO2 but was abandoned after the second cycle.

Figure A.28: Conversion of 16 by 6a-TiO2 after 60 minute cycles of irradiation with 450nm LEDs.

106

Figure A.29: Conversion of 16 by 6b-TiO2 after 60 minute cycles of irradiation with 450nm LEDs.

107

APPENDIX B: SUPPORTING INFORMATION FOR “OXIDATION OF ALKYL BENZENES BY A FLAVIN PHOTOOXIDATION CATALYST ON NANOSTRUCTURED METAL-OXIDE FILMS.”

B.1. SI Methods

B.1.1. Materials.

All of the substrates were purchased from SigmaAldrich and used as received. FMN was purchased from TCI Co. Ltd. in >98% purity and used as received. The cocatalyst MnO2 was purchased from Fluka and used as received. The synthesis of [Fe(TPA)(MeCN)2](ClO4)2 (TPA =

Tris(2-pyridylmethyl)amine) is described in the following sections. A 3-W continuous LED light was purchased from Thor Laboratories provided with a manual light intensity controller.

B.1.2. Preparation of FTO|Oxide-FMN.

FTO was purchased from Hartford Glass with a sheet resistance of 15 Ω/sq. Preparation

165,166 of nanocrystalline ZrO2 or TiO2 over layers on a bare FTO glass was described previously.

Catalyst loading on the surfaces was achieved by techniques developed for related photoelectrodes by immersing the oxide slides in a 0.5 mM methanol solutions of FMN for up to

∼6 h to achieve the highest surface loadings. FMN adsorption isotherms on FTO were measured by soaking the slides for 6 h in methanol solutions of FMN with concentrations of 0.0125, 0.025,

0.05, 0.25, 0.5, and 0.75 mM. The results of a surface-binding study on FTO as a function of

FMN concentration in methanol were analyzed by using the Langmuir adsorption relation in the form Г = Гmax((K[FMN])/(1 + K[FMN])), where Гmax is the maximum surface loading in mol.cm−2 and K is the surface loading constant.167

108

B.1.3. Experimental Setup.

In general, a substrate (0.06 mmol) and cocatalyst (8 mol%) were directly added to 1.5 mL (acetonitrile/ water 1/1 vol/vol) mixture in a 1-dram vial equipped with a magnetic stir bar.

FTO|ZrO2-FMN was immersed in the solution with the setup that allowed full exposure of the visible light from LED light source and the vial was capped with a rubber septum. The mixture was then saturated with oxygen and placed on a stir plate to allow continuous stirring during the course of the reaction.

After the photolysis periods in Table 3.2, the reaction vials were removed with sample analysis by NMR (unless otherwise noted). A UV-vis spectrum of the solution was acquired after each reaction to test for residual FMN in the reaction mixture. No bands arising from FMN were observed. The products were analyzed by NMR with hexamethyldisiloxane (HMDSO) as an internal standard.

B.1.4. Preparation of Fe(TPA) Complex.

The Fe(TPA) complex was prepared similar to a literature procedure.168 Iron(II)triflate

(122 mg, 0.34 mmol, 1 eq) and lithium perchlorate (365 mg, 3.4 mmol, 10 eq) were dissolved in acetonitrile (5 mL). To this solution was added a solution of TPA (100 mg, 0.34 mmol, 1 eq) in acetonitrile (1 mL). The reaction was stirred at room temperature for 3 h and then precipitated in ether. The solid was taken up again in acetonitrile and reprecipitated in ether to give the product as a microcrystalline red solid. A 19F NMR confirmed that there was no remaining triflate. The

1 169 H NMR data are in agreement with the previous literature report : (CD3CN, 400 MHz) δ 10.93

(s, 3H), 8.49 (m, 6H), 7.37 (t, 3H), 6.35 (s, 6H) ppm.

109

B.1.5. UV-Vis Spectra.

All of the absorption spectroscopy was performed using an Agilent 8453 UV-visible spectroscopy system. The resulting data were exported into OriginPro 8.0 for further processing.

−11 −2 Figure B.1. UV-vis of a fully loaded (Γ = 5.7 × 10 mol cm ) FTO|ZrO2-FMN in oxygen- saturated MeCN/H2O (1/1 vol/vol) at room temperature.

110

Figure B.2. UV-vis of FTO|ZrO2-FMN, interval of 5 min in oxygen-saturated MeCN/H2O (1/1 vol/vol) (A) with continuous blue LED irradiation and (B) same experiment in 1,2- dichloroethane at room temperature.

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Figure B.3. Plots of product conversion percent vs. reaction time for (A) ethylbenzene to acetophenone and (B) stilbene to benzaldehyde with FTO|ZrO2-FMN and MnO2 in oxygen- saturated MeCN/H2O 1/1 vol/vol under blue light irradiation (440 nm) at room temperature.

112

Figure B.4. NMR spectra showing the appearance of benzaldehyde upon oxidation of stilbene in the presence of FTO|ZrO2-FMN and MnO2 in oxygen-saturated MeCN/H2O 1/1 vol/vol under blue light irradiation (440 nm) at room temperature.

Figure B.5. NMR spectra showing the appearance of acetophenone upon oxidation of ethylbenzene in the presence of FTO|ZrO2-FMN, MnO2, and 30 mol% of HClO4 in oxygen- saturated MeCN/H2O 1/1 vol/vol under blue light irradiation (440 nm) at room temperature.

113

Table B.1. Substrates for photooxidation by FTO|ZrO2-FMN with added [Fe(TPA)(MeCN)2](ClO4)2 cocatalyst, their corresponding products, reaction times, and product yields in 1:1 H2O/MeCN vol/vol

Standard conditions: 0.06 mmol substrate, 8 mol % FeTPA, 1.5 mL 1:1 H2O:MeCN vol/vol, oxygen-saturated, LED (3 W, 450 nm). The yields were determined using NMR with HMDSO as an internal standard.

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APPENDIX C: SUPPORTING INFORMATION FOR “STRONGER THAN LITHIUM: PHOTOEXCITED ACRIDYL RADICAL AS A SUPER-REDUCTANT FOR SINGLE ELECTRON REDOX CHEMISTRY

C.1 General Methods

Commercially available reagents were purchased from Sigma-Aldrich, Acros, Alfa

Aesar, or TCI, Matrix Scientific, Combi-Blocks, Oakwood Chemical, and Fisher Scientific and were used as received unless otherwise noted. Proton, carbon, and fluorine magnetic resonance spectra were collected on a Bruker model DRX 400, a Bruker Avance III 500, or a Bruker

Avance III 600 CryoProbe (1H NMR at 400 MHz, 500 MHz, and 600 MHz respectively).

Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane

1 and are referenced to residual protium in the solvent ( H NMR: CHCl3 at 7.26 ppm). Chemical shifts for carbon signals are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent peak (13C NMR: CDCl3 at 77.16 ppm). 1H

NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, hept = heptet, dd = doublet of doublets, ddd = doublet of doublet of doublets, m = multiplet, br s = broad singlet, app = apparent), coupling constants (Hz), and integration. 1H

NMR yields were determined using hexamethyldisiloxane (HMDSO) as an internal standard. 19F

NMR yields were determined using hexafluoroisopropanol (HFIP) as an internal standard. EPR spectra were acquired on a JEOL FA-100 spectrometer operating at X–band (9.5 GHz) using a

TE011 cylindrical microwave resonator with 100 kHz field modulation. UV-vis spectra were collected using a Cary50 Bio spectrophotometer. All fluorescence measurements were collected using an Edinburgh FLS920 Spectrometer. Cyclic voltammograms were collected using a Pine

WaveNow Potentiostat. Samples were prepared with 0.05 mmol of substrate in 5 mL of 0.1 M tetra-n-butylammonium hexafluorophosphate (tBAPF6) in dry, degassed acetonitrile.

115

Measurements employed a platinum disk working electrode, platinum wire counter electrode, 3.5

M NaCl silver-silver chloride pseudo-reference electrode, and a typical scan rate of 100 mV/s.

Data analysis was performed in Excel where the E1/2 (or Ep/2 for irreversible redox events) was found and referenced to Ag|AgCl. This value was then converted to SCE by subtraction of 0.03

V. Irradiation of photochemical reactions was carried out using materials purchased from

RapidLED. Ultraviolet UVA LEDs (390-400nm) were mounted upon a NanoTank heatsink and attached to 40o focusing lenses attached to a 3D printed frame that held 1 dram and 2 dram vials above each lens. Reactions were cooled using GDSTIME 3000rpm 12cm by 12cm fans placed on top of the reactor. Stirring was achieved by placing the assembled reactor on a stir plate. All reactions were performed in 1 dram vials and were run under air unless otherwise specified.

Alternatively, reactions performed at longer wavelength were irradiated from the side at a distance of 1–2 cm by a single 467nm Kessil floodlamp with an average intensity of 288mW/cm2

(measured from 1 cm distance). The spectral bandwidth of the 467nm Kessil lamp was estimated to be ± 40nm.

C.2 Electron Paramagnetic Resonance (EPR) measurements

In a nitrogen filled glovebox, a solution of acridinium 2 (54µM in CH3CN) was reduced to acridyl radical 1 by addition of excess cobaltocene. The solution was removed from the glovebox and an EPR spectrum obtained as shown in Figure C.1.

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Figure C.1: EPR spectrum of 1.

C.3 Electrochemical measurements

Cyclic voltammetry was performed as described in section C.1.

Figure C.2: Cyclic voltammogram of 2 in acetonitrile (scan rate = 100mV/s). The ground state oxidation potential of 1 is determined from the E1/2 to be −0.60 V vs. SCE.

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Figure C.3: Cyclic voltammogram of 2 in acetonitrile showing the redox wave for reduction of 1 to 7. E1/2 for this redox event was determined to be −1.64 V vs. SCE.

Figure C.4: Scan rate dependence of the various redox events in cyclic voltammetry of 2. Redox waves are irreversible at high scan rate but become quasi-reversible at low scan rates.

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Figure C.5: Evaluation of non-Nernstian behavior as a function of scan rate in the cyclic voltammetry of 2. (A) Ratio of anodic and cathodic current of each redox event as a function of scan rate. (B) Anodic and cathodic peak separation for each redox event as a function of scan rate. In both cases, quasi-reversible Nernstian behavior is observed at the lowest scan rates. Deviation from ideal Nernstian behavior increases with increasing scan rate.

Figure C.6: Cyclic voltammogram of 4-chlorobenzonitrile in acetonitrile. The Ep/2 was determined to lie at −2.06 V vs. SCE in agreement with literature report.

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C.4 Generation of 1 by photoreaction of 2 and DIPEA

A solution of 2 (50μM) in acetonitrile was made in a nitrogen filled glovebox. Excess

DIPEA (~52μl) was added to this in a quartz cuvette. The cuvette was sealed and brought out of the glovebox and an absorption spectrum recorded. The solution was then irradiated with 450nm

LEDs and absorption spectra recorded at intervals. Clean reduction of 2 to 1 was observed after short irradiation.

Figure C.7: Absorption spectra of 2 in the presence of excess DIPEA prior to irradiation (blue) and 1 generated by 450nm irradiation for 30 seconds (red) and for 60 seconds (green).

C.5 Example reaction setup

General procedure: To a 1 dram vial with stir bar was added 2 (5.7mg, 0.01mmol, 0.1 eq), DIPEA (52μl, 0.3mmol, 3.0 eq.), substrate (0.1mmol), and acetonitrile (0.13ml). The vial was sealed with a septum cap and irradiated with 390nm LEDs for 16 hours. After this time,

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HMDSO (3.5μl, 0.016mmol) and deuterated chloroform (0.4ml) were added and the reaction mixture analyzed by 1H NMR.

C.6 Fluorescence experiments

Samples for emission studies were prepared as follows. Acridinium 2 was brought into a nitrogen filled glovebox and a stock solution in acetonitrile prepared. This solution was reduced to 1 with the addition of cobaltocene. A portion of this sample was taken and diluted to the desired concentration with hexanes, after which the sample was passed through alumina to remove excess cobaltocene, cobaltocenium, and any remaining 2. The solution was added to a cuvette, sealed with septum screw cap, and further sealed with electrical tape. The sample was then removed from the glovebox and absorption and emission spectra were collected. All emission and excitation data for 1 were collected for a sample with an optical density of 0.80 at

512nm with the exception of the emission acquired at 484nm excitation which was collected for a sample with an optical density of 0.27at 512nm. A similar procedure was followed for the generation of acridyl radical 3.

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Figure C.8: Normalized absorption, emission, and excitation spectra of 1 in hexanes. Excitation of the low energy absorption results in normal mirror like emission (red trace). Excitation at 385nm reveals the new high energy emission band (blue trace). The spectral wavelengths between 400–450nm are obscured by a solvent Raman feature and were removed. The excitation spectrum is obtained by monitoring the emission intensity at 555nm (purple trace).

Figure C.9: Excitation spectra collected by monitoring at different emission wavelengths. The emission generated by excitation at 385nm is shown for comparison (blue trace). Because the emission represents the contributions of both emissive excited states, the excitation spectra are wavelength dependent and related to the relative population of each excited state at the chosen wavelength.

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Figure C.10: Spectral deconvolution of the emission generated upon 385nm excitation (blue trace). The high energy emission is fitted to a Gaussian distribution (red trace) and subtracted from the emission spectrum. The subtraction (black trace) is compared to the emission spectrum (purple trace) obtained upon excitation only of the low energy absorption band.

Figure C.11: Normalized absorption and emission spectra for acridyl radical 3. Emission spectrum shown after subtraction of the solvent Raman response. Excitation at 469nm.

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Figure C.12: (A) Emission spectra collected at varying excitation wavelength for acridyl radical 3 in hexanes after subtraction of the solvent Raman response. (B) Emission intensity as a function of excitation wavelength monitored at the maxima of the normal (579nm) and TICT (704nm) emissions.

Figure C.13: Excitation spectra of 3 in hexanes monitored at varying emission wavelength. For the sample monitored at 704nm, the short wavelength range is missing to avoid the large response from second harmonic generation.

C.7 Determination of excited state oxidation potentials

The electronic energies of the two emissive excited states of 1 were estimated from the absorption, emission, and excitation spectra as follows. Eexc for D1 was estimated by averaging

124 the energies of the lowest energy absorption maximum and the highest energy emission maximum observed upon 484nm excitation. However, a similar estimation of ETICT by comparison of the high energy absorption and emission maxima is believed to significantly overestimate the energy of this excited state, particularly as the transition at the absorption maximum does not appear to result in population of the TICT state (compare absorption and excitation spectra in Figure C.8). Instead, ETICT is estimated by averaging the energies of the emission maximum near 490nm and the maximum of the corresponding excitation spectrum monitored at this wavelength. The oxidation potential of each excited state is calculated using equation 2 from the main text. Determination of the ground state oxidation potential is shown in

Figure C.2.

2.42 eV (512nm) + 2.20 eV (564nm) E = = 2.31 eV D1 2

∗ Eox퐷1 = −0.60 V vs. SCE − 2.31 eV = −2.91 V vs. SCE

2.99 eV (414nm) + 2.52 eV (492nm) E = = 2.76 eV TICT 2

∗ EoxTICT = −0.60 V vs. SCE − 2.76 eV = −3.36 V vs. SCE

C.8 Catalyst Preparation

Catalyst 2 was synthesized as reported previously.30

125

The catalyst 9-terphenyl-10-phenylacridinium tetrafluoroborate was prepared by Jeremy

Griffin by a route similar to those published previously.27

Preparation of 9-tertbutyl-10-methyl-9,10-dihydroacridine. In a round bottom flask with stir bar was added 10-methylacridinium iodide (250mg, 0.78mmol, 1.0 eq.) and THF (5 ml).

The material was not entirely soluble in this mixture. To this was added tertbutylmagnesium chloride (0.78ml, 1M, 0.78mmol, 1.0 eq.) and the reaction stirred at room temperature for several hours and then heated to 55 oC overnight. Incomplete conversion was observed by TLC and so another equivalent of Grignard was added followed by an additional half of an equivalent after four hours. The reaction was left to stir overnight again and then was quenched with water, extracted with DCM and the solvent removed to leave an orange yellow solid. Purification by column chromatography (DCM) was performed to yield 0.17g (86%) of an off-white solid confirmed by NMR to be the 9-tertbutyl-10-methyl-9,10-dihydroacridine. 1H NMR (600 MHz,

Chloroform-d) δ 7.33 (td, J = 7.7, 1.6 Hz, 2H), 7.23 (dd, J = 7.5, 1.6 Hz, 2H), 7.04 (td, J = 7.4,

1.0 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 3.71 (s, 1H), 3.42 (s, 3H), 0.89 (s, 9H) ppm. 13C NMR

(151 MHz, CDCl3) δ 143.5, 130.8, 126.9, 124.9, 119.8, 112.1, 54.3, 37.3, 32.9, 27.4 ppm.

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Preparation of 9-tertbutyl-10-methylacridinium tetrafluoroborate (10). Efforts towards oxidation of the dihydroacridine to the acridinium are ongoing.

C.9 Substrate Synthesis

Synthesis and characterization of 4-(4-bromophenyl)-1-butene are reported in Appendix A.

Synthesis of 4-(2-bromophenyl)-1-butene. To a flame dried round bottom flask with stir bar was added 1-bromo-2-(bromomethyl)benzene (1.00 g, 4.00 mmol, 1.0 eq.) and THF (10ml).

The reaction was cooled to 0 oC and allylmagnesium chloride (1.21 g, 6 mL, 3 eq., 12.0 mmol) was added dropwise via addition funnel. The reaction was allowed to warm to room temperature overnight. The solution was then quenched with water and extracted 2x with ether. The solvent was removed, the residue taken back up in ether and washed with water. The organic layer was dried with sodium sulfate, rotovapped, and placed briefly on high vac to yield 0.72g (85%) of a colorless oil. Note: The compound is highly pungent and mildly irritating. Spectral data are in agreement with literature.

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Synthesis of N-Boc-4-chloroaniline. In a 20ml vial, 4-chloroaniline (316mg,

2.418mmol, 1.0 eq.), ditertbutyl dicarbonate (0.58ml, 2.48mmol, 1.0 eq.), and HFIP (3ml) were combined and stirred at room temperature for two days. The solvent was removed and the residue purified by column chromatography (20% EtAc/hexanes) to leave 157mg (28%) of solid product. Spectral data are in agreement with literature.

Synthesis of 4-methoxyphenylacetate. To a flame dried round bottom flask with stir bar, was added 4-methoxyphenol (1.00 g, 1 eq., 8.06 mmol), DCM (20ml), and triethylamine

(1.63 g, 2.2 mL, 2 eq., 16.1 mmol) . Acetyl chloride (1.26 g, 1.15 mL, 2 eq., 16.1 mmol) as a solution in DCM was added dropwise and the reaction was stirred at room temperature overnight. The solution was then washed with 3N HCl, dried with sodium sulfate, and the solvent removed. The residue was purified by column chromatography (DCM) and 1.18g (88%) of a colorless oil was isolated. Spectral data matches those previously reported in the literature.

Synthesis of 4-methoxyphenyltosylate. Combined 4-methoxyphenol (1.00g, 8.06mmol,

1.0 eq.), tosyl chloride (1.56g, 8.18mmol, 1.02 eq.), and cesium carbonate (2.62g, 8.06mmol, 1.0 eq.) in a flame dried round bottom flask with stir bar and stirred at room temperature for 2 hours.

Water was then added and the solution was extracted with ethyl acetate. The organic layer was washed twice with water and once with brine, dried with sodium sulfate and the solvent removed

128 to leave 2.155g (96%) of a white solid. Spectral data matches those previously reported in the literature.

Synthesis of 4-methoxyphenyltriflate. Combined 4-methoxyphenol (248 mg, 1 eq., 2.00 mmol), pyridine (475 mg, 0.48 mL, 3 eq., 6.00 mmol) , and DCM (3ml) in a flame dried round bottom flask with stir bar. Cooled to 0 oC and added trifluoromethanesulfonic anhydride (1.13 g,

676 µL, 2 eq., 4.00 mmol) dropwise. The reaction was allowed to stir at 0 oC for 1 hour and then quenched with addition of water. The reaction mixture was diluted with DCM, washed with saturated sodium bicarb (Note: caution due to gas evolution), and dried with sodium sulfate. The solvent was then removed to yield 0.43g (84%) of a clear colorless oil. Spectral data are in agreement with the literature.

Synthesis of 4-methoxyphenylmesylate. Combined 4-methoxyphenol (248 mg, 1 eq.,

2.00 mmol), pyridine (475 mg, 0.48 mL, 3 eq., 6.00 mmol), and DCM (3ml) in a flame dried round bottom flask with stir bar. The reaction was cooled to 0 oC and methanesulfonyl chloride

(458 mg, 312 µL, 2 eq., 4.00 mmol) was added slowly. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water, diluted with DCM, washed with saturated sodium bicarb, dried with sodium sulfate, and the solvent removed under vacuum to leave a crude solid. The solid was taken back up in DCM and washed twice with saturated aqueous sodium bicarbonate and once with dilute HCl. The organic layer was dried with sodium sulfate and the solvent removed to leave 0.32g (79%) of a white crystalline material. Spectral data are in agreement with the literature.

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Synthesis of (1S)-(+)-10-Camphor-(4-methoxyphenyl)-sulfonate. To a round bottom flask with stir bar was added 4-methoxyphenol (500mg, 4.03mmol, 1.0eq.) and pyridine (10ml).

The reaction was cooled to 0 oC and (1S)-(+)-10-Camphorsulfonyl chloride (1.01g, 4.03mmol,

1.0 eq.) was added. The reaction was allowed to warm to room temperature overnight, but then stirred for an additional day. The reaction was quenched with water, extracted with DCM, and washed with ammonium chloride with the addition of a small amount of 3N HCl. The organic layer was dried with sodium sulfate and the solvent removed to leave a viscous colorless oil.

Purification by column chromatography (DCM) was performed to leave 1.05g (77%) of a white solid. 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J = 9.1 Hz, 2H), 6.90 (d, J = 9.1 Hz, 2H),

3.81 (s, 3H), 3.79 (d, J = 15.1 Hz, 2H), 3.16 (d, J = 15.0 Hz, 1H), 2.60 – 2.52 (m, 1H), 2.42

(dddd, J = 18.5, 4.3, 3.2, 1.0 Hz, 1H), 2.14 (t, J = 4.5 Hz, 1H), 2.12 – 2.04 (m, 1H), 1.71 (ddd, J

= 14.0, 9.4, 4.7 Hz, 1H), 1.45 (ddd, J = 13.1, 9.4, 3.9 Hz, 1H), 1.16 (s, 3H), 0.90 (s, 3H) ppm.

Synthesis of 4-tertbutylphenylmesylate. Combined 4-(tert-butyl)phenol (300 mg, 1 eq.,

2.00 mmol), pyridine (475 mg, 0.48 mL, 3 eq., 6.00 mmol), and DCM (3ml) in a flame dried round bottom flask with stir bar. The reaction was cooled to 0 oC and methanesulfonyl chloride

130 to leave a crude solid. The solid was taken back up in DCM and washed twice with saturated aqueous sodium bicarbonate, dried with sodium sulfate, and the solvent removed to leave 0.39g

(85%) of a pure white solid. Spectral data are in agreement with the literature.

Synthesis of 4-methylcarboxybenzylmesylate. To a dry round bottom flask with stir bar was added methyl (4-hydroxymethyl)benzoate (1g, 6.0mmol, 1.0 eq.) and DCM (40ml). This was cooled to 0 oC and methanesulfonyl chloride (0.51ml, 6.6mmol, 1.1 eq.) was added.

Triethylamine (1.9ml, 13mmol, 2.2 eq.) was added dropwise to this and the reaction was allowed to warm to room temperature over 2 hours. The reaction was quenched with water, the organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine. The solvent was then removed to leave a dark yellow oil which upon sitting crystallized into fine white needles. Further purification was performed by column chromatography to yield 0.69g

(47%) of a white solid. Spectral data are in agreement with the literature.

C.10 Generation of Acridine anion (7) and 9,10-dihydroacridine (6).

In a nitrogen saturated glovebox, 2 was dissolved in THF and excess KC8 was added. The resulting acridine anion (7) was then separated from graphite and residual KC8 by filtration through cotton to leave a colorless solution in THF. This solution was brought out of the glovebox and quenched with addition of 3N aqueous HCl. This solution was then extracted with ether, dried with sodium sulfate, and the solvent removed to leave a colorless solid which was confirmed by NMR to be the 9,10-dihydroacridine (6). 1H NMR matches the off cycle intermediate observed in the dehalogenation reactions.

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Figure C.14: Absorption spectrum of 7 in THF.

1 H NMR (600 MHz) of 9,10-dihydroacridine 6 in CDCl3.

132

13 C NMR (151 MHz) of 9,10-dihydroacridine 6 in CDCl3.

133

HSQC NMR spectrum of 9,10-dihydroacridine 6 in CDCl3.

COSY NMR spectrum of 9,10-dihydroacridine 6 in CDCl3.

134

HMBC NMR spectrum of 9,10-dihydroacridine 6 in CDCl3.

C.11 Spectroelectrochemistry

The absorption spectrum of each oxidation state of the catalyst (2, 1, and 7) were obtained from spectroelectrochemical measurements in acetonitrile containing 0.1M tBAPF6.

The working electrode was a platinum honeycomb microelectrode with a Pt counter (Pine

Research Instruments) and a Ag/AgCl pseudo reference electrode. Spectra were collected using an Avantes AvaLight DHc light source with an Avantes StarLite AvaSpec-2048 UV/vis spectrometer, while the electrochemical potential was applied using a Pine Wavenow potentiostat. All of the devices were controlled using Aftermath software (Pine Research

Instruments). Data were recorded in 50mV intervals from -700mV to -2000mV and back to -

700mV. Notably, the observed spectral changes do not occur at the E1/2 potentials determined separately by cyclic voltammetry. This is a known result of the honeycomb electrode where poor electron transfer kinetics can result in large peak-to-peak splitting and reduction events occur at

135 more negative potentials (converse is true of oxidation events) than those determined by cyclic voltammetry using a traditional platinum disk electrode. Clean reduction of 2 to 1 and 1 to 7 was observed. However, very little 1 or 2 is formed upon return to -700mV. This could be explained by a possible protonation of 7 upon formation (as postulated by Koper for an analogous system) or oxidation to 2 only occurring at a more positive potential than -700mV as a result of the large peak-to-peak splitting mentioned above. It was observed that approximately 20% of 2 could be recovered by applying a potential of +300mV. All spectroelectrochemical measurements were taken with the assistance of Eric Piechota.

Figure C.15: Spectroelectrochemical measurements of 2 in acetonitrile. (A) Reduction of 2 to 1 in 50mV steps. (B) Reduction of 1 to 7 in 50mV steps.

136

Figure C.16: Spectroelectrochemical measurements of 2 from -1900mV to -700mV in 50mV steps after already moving from -700mV to -2000mV in 50mV steps. The red line is the spectrum collected at -700mV. A small growth of 1 is observed until -900mV but decreases with application of more positive potential.

C.12 Mechanistic experiments

In a 1 dram vial with stir bar were combined 4-(2-bromophenyl)-1-butene (8) (21mg,

0.1mmol, 1.0 eq.), 2 (5.7mg, 0.01mmol, 0.1 eq.), DIPEA (52μl, 0.3mmol, 3.0 eq.) and acetonitrile (0.13ml). The vial was sealed with a septum cap and irradiated with 390nm LEDs for

1 10 hours. HMDSO internal standard and CDCl3 were added and the reaction analyzed by H

NMR. Proton NMR shows 71% remaining starting material and approximately 26% of the cyclized product. GCMS confirms starting material and product as the major species present.

The product of simple protodehalogenation, 4-phenyl-1-butene, was not detected.

137

In a 1 dram vial with stir bar were combined 4-bromoanisole (13μl, 0.1mmol, 1.0 eq.), 2

(5.7mg, 0.01mmol, 0.1 eq.), DIPEA (52μl, 0.3mmol, 3.0 eq.), and deuterated acetonitrile

(CD3CN, 0.3ml). The vial was sealed with a septum cap and irradiated with 390nm LEDs for 16 hours. 1H NMR of the reaction mixture shows 83% anisole with 18% returned starting material and no deuterium incorporation into the product. GCMS also confirms no deuterium incorporation.

C.13 Reductive dehalogenation of alkyl halides

In a 1 dram vial with stir bar were combined 11-bromo-1-undecene (22μl, 0.10mmol, 1.0 eq.), 2 (5.7mg, 0.01mmol, 0.1 eq.), DIPEA (52μl, 0.3mmol, 3.0 eq.), and acetonitrile (0.3ml).

The vial was sealed with a septum cap and irradiated with 390nm LEDs for 15 hours. 1H NMR of the reaction mixture shows 34% 1-undecene with 60% returned starting material. GCMS indicates 5-10% of cyclization and dimerization products.

In a 1 dram vial with stir bar were combined methyl 4-bromovalerate (14μl, 0.10mmol,

1.0 eq.), 2 (5.7mg, 0.01mmol, 0.1 eq.), DIPEA (52μl, 0.3mmol, 3.0 eq.), and acetonitrile (0.3ml).

The vial was sealed with a septum cap and irradiated with 390nm LEDs for 15 hours. 1H NMR of the reaction mixture shows approximately 33% methyl valerate with 56-65% returned starting material.

138

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