1 Theoretical Studies of Reactive Intermediates in Complex Reaction Mechanisms Dissertation Presented in Partial Fulfillment Of

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Theoretical Studies of Reactive Intermediates in Complex Reaction Mechanisms

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy

in the Graduate School of The Ohio State University

William H. Coldren

Graduate Program in Chemistry

The Ohio State University

2018

Dissertation Committee

Professor Christopher M. Hadad, Advisor

Professor Jon R. Parquette

Professor David A. Nagib

Professor Karl A. Werbovetz

Copyrighted by

William H. Coldren

2018

Abstract

The mechanistic transformations of three fundamental classes of reactive intermediates are explored: singlet and triplet carbenes, carbene radical cations, and carbon-centered radicals. Through a marriage of theory and ultrafast spectroscopy, the identities of unique carbene species and photochemical transformations were characterized from nitrogenous (diazo and diazirine) precursors. The photochemistry of a novel trifluoro-diazo, carbenic precursor (ethyl 2-diazo-3,3,3-trifluoropropanoate) is explored by ultrafast time-resolved infrared spectroscopy in multiple solvents and the results do not reveal a prototypical 1,2-migration product via rearrangement in the excited state or through a carbene intermediate. The primary photochemical process is the interconversion of a diazo functional group to the corresponding diazirine.

A completely new mechanistic pathway is detailed for the conversion of diazo and diazirine containing nitrogenous precursors to their corresponding products. This theoretical report accounts for the partially unexplained and curious bifurcation in photochemical vs thermal decomposition of nitrogenous precursors.

Using a phenanthrene precursor, the first ultrafast time-resolved spectroscopic observation of a vinyl carbene (singlet a-methylbenzylidenecarbene) is reported and the results are supported and rationalized by computational data.

Electronic factors affecting the regioselectivity of aryl radical hydrogen-atom abstraction reactions in benzyl-alkyl tethered species is explored in order to guide efforts of selective remote C–H functionalizations. The system can be biased towards or away from the standard abstraction pathway by the use of electron-donating and electron- withdrawing groups strategically placed on the benzene ring.

The mechanistic aspects of the oxidative transformation of C2 symmetric o- aminophenol species and C3 symmetric formyl fragments to form benzobisxazole based covalent organic frameworks (COFs). Computational data strongly suggest that such reactions occur via a putative radical species that is stabilized by an active captodative effect. The nature of the catalysts used affects the efficiency of this reaction and the overall crystallinity and porosity of desired COFs.

Preliminary investigations into the difficulty of resurrecting aged huAChE based on the nature of organophosphorus chemical nerve agents are presented. The active site is severely contracted for a methyl phosphonate aged enzyme compared to an alkyl phosphate aged enzyme. In silico prediction of factors influencing the binding and activity of novel quinone methide precursors as potential therapeutics is investigated with biophysical molecular dynamics simulations and in the case of one substrate, the efficacious enantiomer was predicted a priori to experimental in vitro screening.

iii

Dedication

To my parents, John and Karen Coldren, and all of my family and friends, without whom none of my success would be possible.

“He who has a why to live can bear almost any how.”

– Friedrich Nietzsche

“The fundamental laws necessary for the mathematical treatment

of a large part of physics and the whole of chemistry are thus

completely known, and the difficulty lies only in the fact that application of these laws leads to equations that are too complex to be solved.”

– Paul Dirac

Acknowledgments

As I’ve finally reached this moment in time where my graduate career is almost at a close, I am reminded, humbled, and blessed by the many outstanding people who have made my accomplishments possible. This acknowledgment section could take up an entire chapter’s worth of space and still not adequately cover the extent of my gratitude towards all those mentioned. Brevity was never my thing as anyone who knows me could surely tell you (I think the tremendous amount of epic fantasy literature I have read has contributed to this shortcoming), but I will endeavor to do my best. Buckle up…

I would like to thank my mother and father for their constant love, encouragement, patience, and support throughout my life. Their support has allowed me to defeat every obstacle, no matter the size, that has obstructed my path.

To the D’Elias, Mr. and Mrs. D’Elia, Patrick and Becky, Scott and Catherine whom I consider to be as close as family; my gratitude for your selflessness, love, kindness, prayers, and support I cannot sufficiently put into words.

To Dr. Francis Marchlinski, Dr. Anjali Tiku Owens, Monica Pammer, Erica Zado,

Amy Beatty Marzolf, Dr. Stephanie Clouse, and Dr. Heidi Johnson as well as many other talented and compassionate electrophysiologists, nurses, especially my good friend

Rachel Zekany, and the many other healthcare professionals at the University of

Pennsylvania. You helped me through some of the most challenging periods of my life

v and enabled me to live and accomplish my goals and live out my passion. You've instilled in me a desire to do everything that is within my power to help others.

To Mr. Spahr, my first chemistry instructor and one of the most influential instructors I have ever met. I was hooked on the subject from the first day of class. I decided my sophomore year of high school that I was going to study chemistry, and it would be my passion for life. The critical thinking skills you instilled in me, and the sheer amount of talent and excitement you brought to the classroom is something I will take with me wherever I go.

I'd like to thank my undergraduate research advisor Dr. Daniel Falvey and my graduate mentor Dr. Raffaele Perrotta who introduced me to the world of reactive intermediates and computational chemistry and guided me on my way to my graduate studies.

To Dr. Christopher Hadad whose unending patience, unparalleled expertise, guidance, and willingness to help and mentor me throughout my graduate career has entirely enabled the successful completion of my Ph.D. The lessons I have learned I will keep for a lifetime. You have been an absolutely outstanding advisor. I owe you a debt that I can never possibly repay. Thank you, you are an inspiration of excellence.

To Dr. Matthew Platz, my only regret is that our time at OSU didn’t overlap for longer. You are monumental in the field of reactive intermediate chemistry. It has been an absolute pleasure speaking and collaborating with you.

To my graduate teaching mentors, Dr. Christopher Callam and Dr. Noel Paul, your commitment to excellence is an inspiration. You have a fantastic ability to draw out

vi the best in the people around you. Dr. Callam, your love of everything chemistry and tremendous knowledge along with the willingness to discuss life and science has been a blessing.

To the Hadad Group, especially Dr. Hoi Ling (Calvin) Luk, Dr. Shubham Vyas, and Dr. Shameema Oottikkal who spent the time to answer my questions and guided me at the beginning and throughout my graduate career. I’d also like to thank my classmates and colleagues: Dr. Ryan McKenney, Dr. Thomas Corrigan, Dr. Qinggeng Zhuang,

Andrew Franjesivic, Ola Nosseir, Dr. Jojo Joseph, Sarah Border, Dr. Amneh Young, Dr.

Ben Garrett, and Dr. Shane Polen. Also, to the new class of graduate students, especially

Remy Lalisse and Joe Fernandez, may your careers and computational endeavors be fruitful. The thoughtful scientific discussion and support provided by those above was invaluable.

To Dr. Krista Cunningham who cheered me on every step of the way to the finish line, your compassion and friendship is absolutely irreplaceable. Also, to all of my friends that helped me along my journey, putting up with my insanity. Thanks to Ryan

Letourneau and the rest of the gang, your humor helped keep me afloat during my graduate career and while completing this thesis.

A final thanks to the agencies that supported this research: The Ohio

Supercomputing Center, the National Science Foundation, and the National Institutes of

Health.

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Vita

September 21, 1989 ...... Born – Chester County, Pennsylvania USA

June, 2008 ...... Lancaster Catholic High School

May, 2012 ...... B.S., Chemistry, University of Maryland,

College Park

2012–2016 ...... Graduate Teaching Associate, Department

of Chemistry, The Ohio State University

2016–2018 ...... Graduate Research Associate, Department

of Chemistry, The Ohio State University

Publications

1. Perrotta, R. R.; Winter A. H.; Coldren, W. H.; Falvey, D. E. “2-(3,5- Dinitrophenyl)-1,3-dithiane Carbanion: A Benzylic Anion with a Low Energy Triplet State” J. Am. Chem. Soc. 2011, 133, 15553–15558.

2. Kaur, D; Luk, H.; Coldren, W.; Srinivas, P. M.; Sridhar, L.; Prabhakarm S.; Raghunathan, P.; Guru Row, T. N.; Hadad, C. M.; Platz, M. S.; Eswaran, S. V. “Concomitant Nitrene and Carbene Insertion Accompanying Ring Expansion: Spectroscopic, X-ray, and Computational Studies” J. Org. Chem. 2014, 79, 1199– 1205.

3. Feng, C.; Chan, D.; Joseph, J.; Muuronen, M.; Coldren, W. H.; Dai, N.; Correa, I.R.; Fruche, F.; Hadad, C. M.; Spitale, R.C. “Light-activated chemical probing of nucleobase solvent accessibility inside living cells” Nat. Chem. Biol. 2018, 14, 276-283.

viii

4. Pavlović, R. Z.; Mitrović, A.; Coldren, W. H.; Bjelaković, M. S.; Hadad, C. M.; Maslak, V. R.; Milić, D. R. “Cycloaddition Reactions of Azomethine Ylides and 1,3-Dienes on C2v- Symmetrical Pentakisadduct of C60” J. Org. Chem. 2018, 83, 2166–2172.

5. Zhuang, Q; Franjesevic, A. J.; Corrigan, T. S.; Coldren, W. H.; Dicken, R.; Sillart, S.; DeYong, A.; Yoshino, N.; Smith, J.; Fabry, S.; Fitzpatrick, K.; Blanton, T.; Joseph, J.; Yoder, R. J.; McElroy, C. A.; Dogan Ekici, Ö.; Callam, C. S.; Hadad, C. M. “Demonstration of in vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents” J. Med. Chem. 2018. DOI: 10.1021/acs.jmedchem.7b01620

6. Pyles, D. A.; Coldren, W. H.; Eder, G. M.; Hadad, C. M.; McGrier, P. L. “Mechanistic Investigations into the Cyclization and Crystallization of Benzobisoxazole-linked Two-dimensional Covalent Organic Frameworks” Chem. Sci. 2018. DOI: 10.1039/C8SC01683F

Fields of Study

Major Field: Chemistry

Table of Contents

Abstract ...... ii

Dedication ...... iv

Acknowledgments ...... v

Vita ...... viii

List of Tables ...... xiv

List of Figures ...... xx

Chapter 1. Introduction ...... 1

1.1 Preamble ...... 1

1.2 Reactive Intermediates ...... 2

1.2.1 Carbenes ...... 3

1.2.2 Radical Ions ...... 10

1.3 Overview of Chapters ...... 13

1.4 Concluding Remarks ...... 16

1.5 References for Chapter 1 ...... 17

Chapter 2. A Computational Study of the Photochemistry of Ethyl 2-Diazo-3,3,3-

Trifluoropropanoate ...... 23

2.1 Introduction ...... 23

2.2 Computational Methodology ...... 26

2.3 Results ...... 27

2.4 Conclusions ...... 52

2.5 References for Chapter 2 ...... 53

Chapter 3. A Closer Look at Rearrangement in the Excited State of Nitrogenous Carbene

Precursors: Radical Cation-like Behavior? ...... 56

3.1 Introduction ...... 56

3.2 Computational Methods ...... 69

3.3 Migration Pathways for Ethylmethylcarbene and its Radical Cationic Form...... 72

3.4 Product Distributions of Ethylphenylcarbene and its Radical Cationic Form ...... 84

3.5 Results from Benzylchlorocarbene, Chloromethyl-chlorocarbene, and tert-

butylcarbene ...... 93

3.6 Conclusions ...... 101

3.7 References for Chapter 3 ...... 102

Chapter 4. Direct Observation of an Alkylidenecarbene by Ultrafast Transient Absorption

Spectroscopy ...... 108

4.1 Introduction ...... 108 xi

4.2 Computational Methods ...... 110

4.3 Results ...... 110

4.5 Conclusion ...... 124

4.6 References for Chapter 4 ...... 124

Chapter 5. Electronic Effects on the Regioselectivity of Hydrogen-atom Abstraction

Reactions for Tethered Arene Systems ...... 127

5.1 Introduction ...... 127

5.2 Computational Methods ...... 133

5.3 Unsubstituted Aryl Systems with Different Linkers ...... 134

5.4 Influence of Substituents on the Selectivity of Hydrogen-Atom Transfer ...... 148

5.5 Conclusions and Outlook ...... 152

5.6 References for Chapter 5 ...... 153

Chapter 6. Radical Intermediates and their Role in the Formation of Covalent Organic

Frameworks with Benzo-bis-oxazole Building Blocks ...... 156

6.1 Introduction ...... 156

6.2 Computational Methods ...... 162

6.3 Radical Benzoxazole Cyclization: Bond Dissociation Energies, Natural Population

Analysis, and Captodative Stabilization of Intermediates ...... 163

6.4 BBO-COF 2 and BBO-COF 3: Barriers to Self-Assembly ...... 169

xii

6.5 Conclusions and Outlook ...... 171

6.6 References for Chapter 6 ...... 172

Chapter 7. Computational Complexities of Discovering Therapeutics for Aged Human

Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents .... 175

7.1 Introduction ...... 175

7.2 Relevant Crystal Structures ...... 180

7.3 Crystal Structure Preparation ...... 181

7.4 The Active Site of Authentic Nerve Agent vs. OP Pesticide Inhibited huAChE .. 186

7.5 The Protonation States of QMPs and the Thermodynamics of Quinone Methide

Formation ...... 188

7.6 Examining the Molecular Dynamics for Ligand-Protein Complexes: a priori

Performance Prediction? ...... 193

7.7 Establishing a Method to Evaluate Close Contacts During Molecular Dynamics

Simulations...... 201

7.8 Conclusions and Future Perspective ...... 206

7.9 References for Chapter 7 ...... 209

Bibliography ...... 215

References ...... 215

xiii

List of Tables

Table 1.1 Product Distributions (%) from Photolysis and Thermolysis of 3-Ethyl-3-

Methyldiazirine as a Precursor.40 ...... 12

Table 2.1 Calculation of % population of diazoester conformations based on calculated free energies (B3LYP/6-311+G(d,p), CHCl3)...... 29

Table 2.2 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation Z1...... 30

Table 2.3 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation E2...... 30

Table 2.4 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation Z3...... 31

Table 2.5 Calculation of percentage population of diazirine conformations based on calculated free energies in chloroform...... 35

Table 2.6 Calculation of % population of diazoester conformations based on calculated free energies in acetonitrile...... 41

Table 2.7 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine conformation Z1 in acetonitrile...... 42

Table 2.8 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine conformation E2 in acetonitrile...... 42 xiv

Table 2.9 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine Z3 conformer in acetonitrile...... 43

Table 3.1 Product Distributions (%) from Photolysis and Thermolysis of 3-Ethyl-3-

Methyldiazirine as a Precursor.9 ...... 58

Table 3.2 Computed activation barriers (kcal/mol) for the transition states located from the closed–shell EMC to observed thermal products.a ...... 73

Table 3.3 Percent yields for the thermal decomposition of 3-ethyl-3-methyldiazirine from theoretical calculations and experiment.a ...... 73

Table 3.4 Computed activation barriers (kcal/mol) for the transition states located from ethylmethylcarbene’s radical cation relative to the observed thermal products.a ...... 75

Table 3.5 Predicted percent yields for the photochemical decomposition of 3-ethyl-3- methyldiazirine produced by rearrangement on the carbene radical cation surface from theoretical calculations and experimental photolysis data.a ...... 75

Table 3.6 Select bond angles and distances for the transition state leading to 1–butene predicted at the B3LYP/6–31+G(d) level of theory...... 79

Table 3.7 Select bond angles and distances for the transition state leading to trans-2- butene predicted at the B3LYP/6–31+G(d) level of theory...... 80

Table 3.8 Select bond angles and distances for the transition state leading to cis-2-butene predicted at the B3LYP/6–31+G(d) level of theory...... 81

Table 3.9 Vertical excitation energies (TD-B3LYP/6-31+G(d), nm) of the (1– diazopropyl)benzene precursor...... 86

Table 3.10 Computed activation barriers (kcal/mol) for the transition states located on the closed-shell ethylphenylcarbene (EPC) surface.a ...... 87

Table 3.11 Percent distributions based on activation barriers on the closed-shell carbene surface of ethylphenylcarbene (EPC) compared to estimates from experiment.a ...... 88

Table 3.12 Computed relative energies (kcal/mol) for the transition states located on the radical cation surface of the ethylphenylcarbene (EPC) framework...... 88

Table 3.13 Predicted percent yields for the photochemical decomposition of (1– diazopropyl)benzene considered as a rearrangement on the radical cation surface from theoretical calculations and experimental photolysis data.a ...... 88

Table 3.14 Select bond angles and distances for the transition state leading to cis- methylstyrene predicted at the B3LYP/6–31+G(d) level of theory...... 90

Table 3.15 Select bond angles and distances for the transition state leading to trans- methylstyrene predicted at the B3LYP/6–31+G(d) level of theory...... 90

Table 3.16 Computed Activation Barriers (kcal/mol) for the transition states located from the closed-shell benzylchlorocarbene to observed thermal products.a ...... 95

Table 3.17 Percent distributions based on activation barriers on the closed-shell carbene surface of benzylchlorocarbene compared to estimates from experimental thermolysis.a 95

Table 3.18 Theoretical results from calculations on the radical cation surface of benzylchlorocarbene.a ...... 95

Table 3.19 Percent distributions based on activation barriers on the closed-shell carbene surface of benzylchlorocarbene compared to estimates from experimental photolysis.a .. 95

xvi

Table 3.20 Theoretical results from calculations on the neutral carbene surface of chloromethyl-chlorocarbene.a ...... 97

Table 3.21 Predicted percent yields for the thermal decomposition of chloromethyl- chloro carbene from theoretical calculations and experimental pyrolysis data.a,b ...... 97

Table 3.22 Theoretical results from calculations on the radical cation surface of chloromethyl-chlorocarbene.a ...... 97

Table 3.23 Predicted percent yields for the photochemical decomposition of chloromethyl-chloro carbene from theoretical calculations on the radical cation surface as well as experimental photolysis data.a,b ...... 98

Table 3.24 Comparison of product distributions from theoretical calculations and experimental pyrolysis of tert-butyldiazirine (calculations on the neutral carbene surface).

...... 100

Table 3.25 Comparison of product distributions from theoretical calculations and experimental photolysis of tert-butyldiazirine (calculations on the carbene radical cation surface)...... 100

Table 4.1 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) of precursor

1 ...... 112

Table 4.2 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)) for the relaxed S1 state of 1 ...... 113

Table 4.3 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for the relaxed S1 state of 1 ...... 114

Table 4.4 Final one electron symbolic density matrix for 12-pl...... 115

xvii

Table 4.5 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)) for species 12-pl. .. 118

Table 4.6 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species

12-pl...... 118

Table 4.7 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)), for species 12-npl.

...... 119

Table 4.8 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species

12-npl...... 119

Table 4.9 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species 3.

...... 123

Table 5.1 Computed B3LYP/6-31+G(d) hydrogen-atom abstraction barriers for alkyl- tethered species 5.4a...... 135

Table 5.2 B3LYP/6-31+G(d) transition state barriers for 5.4a relative to the lowest energy abstraction at “C2”...... 136

Table 5.3 Computed B3LYP/6-31+G(d) hydrogen abstraction barriers for sulfonate- tethered species 5.4b...... 140

Table 5.4 B3LYP/6-31+G(d) transition state barriers for 5.4b relative to the lowest energy abstraction at C3...... 140

Table 5.5 Computed B3LYP/6-31+G(d) hydrogen abstraction barriers for silyl-tethered species 5.4c...... 143

Table 5.6 B3LYP/6-31+G(d) transition state barriers for 5.4c relative to the lowest energy abstraction at C1...... 144

xviii

‡ Table 5.7 d∆H0 values (B3LYP/6-31+G(d)) for monosubstituted sulfonate-tethered compounds.a ...... 149

‡ Table 5.8 d∆G298 values (B3LYP/6-31+G(d)) for monosubstituted sulfonate-tethered compounds.a ...... 149

‡ Table 5.9 d∆H0 values (B3LYP/6-31+G(d)) for disubstituted sulfonate-tethered compounds.a ...... 151

‡ Table 5.10 d∆G298 values (B3LYP/6-31+G(d)) for disubstituted sulfonate-tethered compounds.a ...... 151

Table 6.1 Experimental yields of BBO-COF 2 dependent upon nucleophilic catalyst. . 160

Table 6.2 Experimental yields of BBO-COF 3 dependent upon nucleophilic catalyst. . 160

Table 6.3 Experimental oxazole yields for model system (Figure 6.7) ...... 166

Table 6.4 Spin population analysis for BBO-COF 2. The calculated structure with a single electron on the a-carbon is shown on the right...... 167

Table 6.5 Spin population analysis for BBO-COF 3. The calculated structure with a single electron on the a-carbon is shown on the right...... 167

Table 7.1 Calculated free energies of formation for select QMs for the decomposition of select QMPs to their quinone methides and the corresponding amine (B3LYP/6-31+G(d),

H2O, SMD)...... 193

xix

List of Figures

+ Figure 1.1 Comparison of methylene (CH2) and protonated imidogen (NH2 ), the simplest carbene and nitrenium ion, respectively...... 3

Figure 1.2 Depiction of the frontier orbitals of methylene with each possible electron configuration: closed-shell singlet (CSS), open-shell singlet (OSS) and triplet states. In the case of methylene, the triplet is actually the ground state configuration.21 ...... 4

Figure 1.3 Summary of stereochemical outcomes from the reaction of different multiplicity carbenes with alkenes. In the case where triplet multiplicity is indicated, a sensitizer was added to the reaction so there is no guarantee that the reactive carbene is purely of the multiplicity listed; nevertheless, the results follow the hypothesis.26 ...... 6

Figure 1.4 A C–H insertion reaction (1,2-H migration) that was experimentally shown to bypass the typical carbene intermediate.43 ...... 7

Figure 1.5 Select, “famous” N-heterocyclic carbenes...... 9

Figure 1.6 Depiction for the photochemical creation of a radical ion pair from a diazirine precursor via a Rydberg excited state...... 10

Figure 2.1 Proposed photochemical pathways based on experimental and computational evidence...... 25

Figure 2.2 Steady state IR absorption (FTIR) of CF3CN2CO2Et in chloroform in the spectral range of 1650 – 2200 cm-1 together with calculated frequencies (scaled and normalized) for different conformers of precursor...... 28

Figure 2.3 Optimized geometries (B3LYP/6-311+G(d,p), CHCl3) of diazoester

(CF3CN2CO2Et) conformations...... 28

Figure 2.4 (a) TRIR spectra recorded for CF3CN2CO2Et in chloroform upon excitation with the 260 nm light (recovery of diazo stretch). Normalized FTIR spectrum is shown as dotted line. (b) Kinetics recorded at 2135 cm-1 (recovery of the ground state) with the fit of one-exponential function: (FIC = A1/(A1 + offset) = 0.56)...... 32

Figure 2.5 TRIR spectra recorded for CF3CN2CO2Et in chloroform upon excitation with the 260 nm light. The time delays for (a) and (b) are the same. Also, the time delays for

Figure 2.6 Steady state UV-vis photolysis of CF3CN2CO2Et in CHCl3 (OD=0.89 at 266 nm) with 260 nm light...... 34

Figure 2.7 Optimized geometries (B3LYP/6-311+G(d,p), CHCl3) of diazirine

(CF3CN2CO2Et) conformations...... 35

Figure 2.8 Steady state photolysis of CF3CN2CO2Et in CHCl3 (a) The decay of precursor monitored on C=N2 vibration. (b) Spectral changes observed in the spectral range of C=O vibration (decay of C=O vibration of precursor and alkene formation). (c) Precursor consumption vs. time of irradiation. (d) FTIR difference spectra. Difference FTIR for given time of irradiation was calculated as the difference between spectrum after irradiation minus scaled FTIR prior irradiation. Scaling factors were calculated based on

xxi precursor consumption taken from plot (c). (e) Relative efficiency of product formation vs. precursor consumption...... 37

Figure 2.9 Diazirine and C–Cl insertion product formation upon photolysis of

CF3CN2CO2Et in CHCl3 with 260 nm light for (a) delays up to 78 ps and (b) for delays longer than 78 ps. Normalized FTIR spectra of CF3CN2CO2Et are shown as dotted lines.

(c) Kinetics recorded at 1720 cm-1 (the recovery of the ground state) and (d) kinetics recorded at 1750 cm-1 (diazirine and C–Cl insertion product formation)...... 39

Figure 2.10 Transition state of 1,2-F shift of CF3CN2CO2Et (B3LYP/6-311+G(d,p)) .... 40

Precursor consumption vs. time of irradiation. (d) FTIR difference spectra. Difference

FTIR for given time of irradiation was calculated as the difference between spectrum after irradiation minus scaled FTIR prior irradiation. Scaling factors were calculated based on precursor consumption taken from plot (c). (e) Relative efficiency of products formation vs. precursor consumption...... 44

Figure 2.12 TRIR spectra recorded for CF3CN2CO2Et in acetonitrile upon excitation with the 260 nm light. Normalized FTIR spectrum is shown as dotted line. (a,b) Recovery of diazo stretch. Kinetics recorded at 2135 cm-1 (recovery of the ground state) with the fit of one-exponential function: (FIC=A1/(A1+offset)=0.55).(c,d) Singlet carbene decay and acetonitrile ylide formation. (e,f) Diazirine formation...... 45

xxii

Figure 2.13 Steady state UV-vis photolysis of CF3CN2CO2Et in MeCN (OD=0.85 @266 nm) with 260 nm light...... 47

Figure 2.14 TRIR spectra recorded for CF3CN2CO2Et in MeOD upon excitation with the

260 nm light for different times of delay (a-c). The transient band at 1618 cm-1 is assigned to the alcohol ylide...... 48

Figure 2.15 Photolysis of CF3CN2CO2Et in MeOD (lexc=260 nm). Kinetics recorded at

1618 cm-1. Alcohol-ylide formation and decay...... 49

Figure 2.16 Diazirine formation upon photolysis of CF3CN2CO2Et in MeOD with 260 nm light for (a) delays up to 45 ps and (b) for delays longer than 45 ps. Normalized FTIR spectra are shown as dotted lines...... 50

Figure 2.17 TRIR spectra recorded for CF3CN2CO2Et in MeOH upon excitation with the

260 nm light (recovery of diazo stretch). Normalized FTIR spectra of CF3CN2CO2Et in

MeOH are shown as dotted lines...... 51

Figure 2.18 Photolysis of CF3CN2CO2Et in MeOH (lexc=260 nm). Kinetics recorded at

2137 cm-1in MeOH (the recovery of the ground state of precursor) with the fit of one- exponential function: (FIC=A1/(A1+offset)=0.61)...... 51

Figure 3.1 Shi’s asymmetric Simmons-Smith modification.8...... 57

Figure 3.2 Examples of nitrogenous precursors that yield different product results upon thermolysis and photolysis...... 59

Figure 3.3 Rearrangement vs intramolecular reaction of chloromethyl-chlorocarbene

(CMCC)...... 61

xxiii

Figure 3.4 All possible electron configurations for a (2e,2o) active space where the two central configurations are isoenergetic because the particles are fermions. The two central configurations would be combined into one CSF that is doubly weighted by a program like Gaussian ’16...... 64

Figure 3.5 Summary of pathways leading from 3-ethyl-3-methyldiazirine to all rearrangement products. Red and blue structures indicate that a large percentage of these is expected to arise from the non-relaxed carbene pathway leading to them...... 66

Figure 3.6 Proposed pathway for observed product formation in hydroxylic media.26 ... 67

Figure 3.7 Photolysis of TME yields rearranged products.26 ...... 67

Figure 3.8 Depiction for the photochemical creation of a radical ion pair from a diazirine precursor via a Rydberg excited state...... 69

Figure 3.9 Optimized geometries of the closed-shell singlet and the radical cation at the

B3LYP/6-31+G(d) level of theory. The open-shell S1 singlet optimized at the

CASCCF(8e,8o)/cc-pVTZ level of theory24 is presented in the bottom row...... 78

Figure 3.10 Transition states calculated at the B3LYP/6-31+G(d) level of theory, leading to 1-butene, trans-2-butene, and cis-2-butene, respectively, from left to right. The first row contains neutral carbene surface geometries and the second row shows geometries of the carbene radical cation surface...... 79

Figure 3.11 Transition states at the B3LYP/6-31+G(d) level of theory, leading to methylcyclopropane and isobutene from left to right, respectively. The first row contains neutral carbene surface geometries and the second row shows geometries of the radical cation surface...... 82

xxiv

Figure 3.12 Predicted reaction pathways for the photolysis of (1-diazopropyl)benzene to cis and trans products...... 84

Figure 3.13 Ratio of cis to trans product as a function of wavelength for the photolysis of

(1-diazopropyl)benzene...... 85

Figure 3.14 Comparison of cis and trans transition states for 1,2-H migration on the neutral carbene and radical cation surface optimized at the B3LYP/6–31+G(d) level of theory. The first row contains neutral carbene surface geometries and the second row shows geometries of the radical cation surface...... 89

Figure 3.15 EPC, radical cation transition state to trans product, showing the SOMO sp2- like orbital on the carbenic center orthogonal to the plane of the benzene ring. Picture without surface for clarity and comparison on right...... 91

Figure 3.16 EPC, neutral carbene transition state to trans product, showing the LUMO with the p-type orbital on the carbene center orthogonal to the plane of the benzene ring.

A structure without the overlapping surface is provided for clarity and comparison on the right...... 92

Figure 3.17 Benzylchlorocarbene, chloromethyl-chlorocarbene, and tert-butylcarbene as formed from the corresponding diazirine compounds...... 93

Figure 3.18 Computationally studied structures with no distinguishing features between photolysis and pyrolysis...... 101

Figure 4.1 Photochemical conversion of 1-(1-phenylethylidene)-1a,9b-dihydro-1H- cyclopropa[l]-phenanthrene (1) to phenylpropyne (3) through a predicted vinyl carbene intermediate (2)...... 109

xxv

Figure 4.2 The fs-TA UV-vis spectra of precursor 1 obtained after 267 nm excitation in

MeCN are shown...... 111

Figure 4.3 Optimized ground state structure of 1 and its optimized, relaxed S1 excited state respectively at the (TD-B3LYP/6-311+G(d,p), SMD, CH3CN) level of theory. ... 113

Figure 4.4 Optimized active orbitals for species 12-pl at the CASSCF(10,10)/6-

311+G(d,p) level of theory...... 115

Figure 4.5 Optimized geometries of carbene 12-npl in the gas phase (left) and acetonitrile

(right)...... 116

Figure 4.6 Computed UV-vis spectrum (TD-B3LYP/6-311+G(d,p), CH3CN) of planar

(black) and nonplanar (red) carbene 12...... 120

Figure 4.7 Computed (top) UV-vis spectrum (TD-B3LYP/6-311+G(d,p), CH3CN) and the observed (bottom) fs-TA spectrum at 12 ps in MeCN solution of non-planar carbene

12...... 121

Figure 4.8 Kinetics at 372 nm of precursor 1 after excitation by 267 nm are shown. The solid red line indicates a fitting of the data using a single exponential function...... 122

Figure 4.9 Kinetics at 325 nm of precursor 1 after excitation by 267 nm are shown. The solid red line indicates a fitting of the data using a single exponential function...... 123

Figure 5.1 Reaction of substituted “portable desaturase” to provide a selective endocyclic alkene and the saturated analog in a 10:1 ratio.8 ...... 130

Figure 5.2 Proposed abstraction pathways for guided desaturation of unactivated, saturated alcohols.11 ...... 132

xxvi

Figure 5.3 Examples of functionalized alcohols using Parasram et al.’s Pd-catalyzed hydrogen abstraction methodology.11 Solid double bonds indicate the major product while the hashed double bonds indicate minor regioisomers. Red, pink, and blue colors indicate results of g-/d-, b-/g-, and d-/e- abstractions, respectively, as defined in Figure 5.2...... 133

Figure 5.4 Structures used as models to predict regioselective abstraction in tethered compounds. Carbons have been numbered for convenience starting at one and continuing to the end of the alkyl chain. Carbons circled in red display the kinetically preferred abstraction location based upon free energy barriers calculated at the B3LYP/6-31+G(d) level of theory...... 135

Figure 5.5 Optimized “C1” abstraction transition state for species 5.4a accompanied by geometric data...... 138

Figure 5.6 Optimized “C2” abstraction transition state for species 5.4a along with select geometric data...... 138

Figure 5.7 Optimized “C3” abstraction transition state for species 5.4a along with select geometric data...... 139

Figure 5.8 Optimized C1 abstraction transition state for species 5.4b along with select geometric data...... 142

Figure 5.9 Optimized C2 abstraction transition state for species 5.4b along with select geometric data...... 142

Figure 5.10 Optimized C3 abstraction transition state for species 5.4b along with select geometric data...... 143

xxvii

Figure 5.11 Optimized C1 abstraction transition state for species 5.4c along with select geometric data...... 145

Figure 5.12 Optimized C2 abstraction transition state for species 5.4c along with select geometric data...... 145

Figure 5.13 Optimized C3 abstraction transition state for species 5.4c along with select geometric data...... 146

Figure 5.14 Starting material and products reaction scheme utilized to calculate relative bond dissociation energies...... 147

Figure 5.15 Monosubstituted model systems for hydrogen atom transfer reactions. Ring numbering begins at the tethered position and proceeds in the direction of the radical. 148

Figure 5.16 Disubstituted model systems for hydrogen atom transfer reactions. Ring numbering begins at the tethered position and proceeds in the direction of the radical. 150

Figure 6.1 BBO-COF 2 and BBO-COF 3 scaffolds and synthetic conditions ...... 157

Figure 6.2 Direct nucleophilic cyclization following Baldwin’s rules ...... 158

Figure 6.3 Partial proposed aerobic, radical pathway and select electronic examples showing captodative stabilization ...... 159

Figure 6.4 Normalized PXRD data (BBO-COF 2 and 3, respectively) ...... 160

Figure 6.5 Molecular scaffolds of computationally investigated substrates ...... 161

Figure 6.6 Structural comparison of distinct azide conformations ...... 164

Figure 6.7 Model system for nucleophile dependent benzoxazole formation...... 166

xxviii

Figure 7.1 Select organophosphorus nerve agents: both phosphonates and phosphates are shown. Compound A-232 was implicated in the recent poisoning of an ex-Russian spy in

Great Britain.1 ...... 176

Figure 7.2 Cycle of acetylcholinesterase reactivity with organophosphorus nerve agents.17 ...... 178

Figure 7.3 Select lead compound 7.3-(R) for resurrecting acetylcholinesterase and its almost completely inactive enantiomer 7.3-(S)...... 180

Figure 7.4 Starting phosphylated serine fragment for optimization and charge calculations...... 183

Figure 7.5 Graphical depiction of area used to calculate active space volume. The view is down the enzyme’s gorge mouth...... 187

Figure 7.6 Different protonation states to consider for QMP C8...... 188

Figure 7.7 UV-vis spectra of compound C8 as the pH is changed from 6-9.16 ...... 190

Figure 7.8 All net neutral protonation states for compound 7.3-(R)...... 191

Figure 7.9 Theoretical decomposition of QMP 7.3-(R) to the corresponding quinone methide intermediate and the chiral amine as the leaving group...... 192

Figure 7.10 Quinone methide precursors selected for QM formation calculations...... 192

Figure 7.11 10 ns simulation showing the relative distance for the net anionic ligand’s benzylic carbon to the “nucleophilic” oxygen oriented in the center of the active site. . 195

Figure 7.12 10 ns simulation showing the relative distance for the net neutral (non- zwitterionic) ligand’s benzylic carbon to the “nucleophilic” oxygen oriented in the center of the active site...... 196

xxix

Figure 7.13 10 ns simulation showing the relative distance for the zwitterionic

(pyridinium) ligand’s benzylic carbon to the “nucleophilic” oxygen oriented in the center of the active site...... 196

Figure 7.14 10 ns simulation showing the relative distance for the zwitterionic

(pyrrolidinium) ligand’s benzylic carbon to the “nucleophilic” oxygen oriented in the center of the active site...... 197

Figure 7.15 Relative resurrection yield of several potential substrates including the enantiomerically pure 7.3-(R) and 7.3-(S) after 24 hours. Screening data was performed in DFP-aged huAChE...... 199

Figure 7.16 Two different views of the DFP-aged huAChE active site with select residues highlighted and utilized for close contact evaluation...... 202

Figure 7.17 Heat map analysis of compound 7.3-(S) in the zwitterionic pyrrolidinium state from a 100 ns MD simulation...... 203

Figure 7.18 Heat map analysis of compound 7.3-(R) in the zwitterionic pyrrolidinium state from a 100 ns MD simulation...... 204

Figure 7.19 Heat map analysis of compound 7.10a in the zwitterionic pyrrolidinium state from a 100 ns MD simulation...... 204

xxx

Chapter 1. Introduction

1.1 Preamble

The material covered in this thesis spans a wide variety of topics and is particularly focused on the nature of reactive intermediates and their roles in various transformations and mechanisms. Theoretical chemistry has played a critical role in lending insight to the mechanistic aspects of these various reactions especially in the case when the investigation of such species uses ultrafast laser spectroscopy or other spectroscopic techniques. The ability to predict, with a relative amount of accuracy, the properties of molecules greatly complements experimental endeavors, and there are many improvements in science due to the synergistic work of theory and experiment. It is beautiful when theory and experiment work hand in hand, and it is most amazing and useful when in silico methods are able to guide the efforts of synthetic chemists expeditiously toward their goals.

A guidance computer with around 4 kB of memory took humanity to the moon in

July of 1969.1 Today it takes a recommended 2 GB (500,000 times more memory) to run the most simple, popular social media apps (imagine if all people used their smart phones for research).2 Computational technology and processing has progressed at an amazing rate and with tremendous benefit to both leisure activities and scientific research. We continue to reach new heights of accuracy and are able to treat larger and more

1 complicated systems rigorously and in a reasonable amount of time with advances in computing technology, something that has made the following research possible.

1.2 Reactive Intermediates

There are an abundant amount of texts and review articles that detail the scientific pursuits of reactive intermediates and carbene chemistry.3–11 As reactive intermediates play a role in the vast majority of organic chemical reactions, understanding their behavior plays a key role in understanding the step-by-step mechanisms through which the reactions proceed. Understanding all of the bond-breaking and bond-forming events for reactions can only help in the pursuit of functionalizing molecules for specific purposes whether it be for materials technology (such as photolithography), pharmaceuticals, environmental and clean energy applications, etc.

The focus of this dissertation is on carbenes, radicals, and radical ions. While nitrenes and nitrenium ions will not be addressed in the main body of this thesis, these too are interesting reactive species that are the subject of two articles worked on and published concurrently with the research described in thesis.12,13 Nitrenes and nitrenium ions will be touched upon briefly in order to compare and contrast with the species that represent the bulk of this work. Nitrenes and nitrenium ions are discussed in a few of the previously cited references, most notably, in Reactive Intermediate Chemistry and other publications by Platz.4,7,8 These intermediates are also extensively reviewed by Wentrup,

Falvey, and McClelland.14–17

1.2.1 Carbenes

The simplest carbene is methylene (CH2); its unselective reactivity was first reported by Doering et al. in 1956.18 Carbenes are divalent carbon species; in the case of methylene, there are two hydrogens attached to a carbon center and two additional electrons. Carbenes are isoelectronic to nitrenium ions, the simplest nitrenium ion being

+ protonated imidogen (NH2 ); however, in contrast to carbenes, the nitrogen center is formally positive (Figure 1.1). Carbenes and nitrenium ions lack a pair of electrons that would produce a full octet. Carbenes are generally known to be ambiphiles.19

C N H H H H

+ Figure 1.1 Comparison of methylene (CH2) and protonated imidogen (NH2 ), the simplest carbene and nitrenium ion, respectively.

Although isoelectronic, the reactivities of these species differ, nitrenium ions essentially react as nitrogen-centered electrophiles. Nitrenium ions, especially aryl nitrenium ions, are reported to be key intermediates in mechanisms that damage nucleic acids, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). This process starts with an amine that is enzymatically oxidized forming a nitrenium ion in vivo which becomes covalently linked to a DNA nucleobase, thereby leading to strand breaks and eventually cancer.20 The reactivity of nicotinoyl azide as a photochemical RNA probe, the focus of a recent collaboration of this group with Spitale et al.,13 is reported to follow

3 an analogous mechanism to that described above. Nicotinoyl azide is photolyzed to form the corresponding nitrene which is then protonated by the solvent, thus forming a nitrenium ion that covalently links to RNA.

Many of these reactive intermediates find their complexity in various electron configurations that are accessible to them. With two available orbitals and only two electrons, carbenes can adopt what are termed a closed-shell singlet (CSS), an open-shell singlet (OSS), and a triplet configuration (Figure 1.2). The reactivity of the molecule depends on this spin multiplicity (as is the case for nitrenes and nitrenium ions).8 In the case of methylene, the triplet is actually the ground state configuration.21 Depending on the substituents at the carbene center, the ground state can change as the geometric and electronic preferences of the central carbene center is different for the CSS, OSS and triplet states of the respective carbene.

H H H

CSS Methylene OSS Methylene Triplet Methylene

The multiplicity and reactivity of carbene species can be biased by the substituents attached to the carbene center.22 Bulky substituents, as in the case of di-

4 adamantylcarbene, produces a carbene-centered bond angle of 143° in solution and thus is biased to the triplet state as the ground state.23 The bond angles of singlet and triplet carbenes tend to differ by a noticeable amount: singlet methylene has a value of ~102° and triplet methylene is ~137°.24 The singlet state of the carbene can be stabilized by substituents with lone pairs bonded to the carbene center as is the case of difluorocarbene. For CF2, the lone pairs on fluorine donate into the empty p-type orbital on the carbene center, thereby stabilizing the closed-shell singlet (CSS) configuration.

The difference in energy between the singlet and the triplet, in the case of CF2, is in favor of the singlet by 57 kcal/mol.25

A straightforward example of how a carbene’s multiplicity can impact its reactivity is shown by the differences in stereochemical outcomes for the addition of carbenes to alkenes to afford cyclopropanes. The reaction of singlet carbenes with alkenes is generally considered to be concerted and is stereospecific, retaining the relative stereochemical relationship of the alkene substituents; thus, a cis-alkene would generate a cis-cyclopropane product. In the case of the triplet carbene, addition to an alkene occurs in a stepwise fashion and causes the stereochemistry to generate a mixture of cis and trans products (Figure 1.3). This reactivity was shown definitively in the case of methylene by Turro et al.26

H 40 < 1 H

H 44 51 H

H < 1 38 H

H 18 79 H

Thus, when predicting the spectra and reactivity of carbenes as intermediates, the electron configuration of such species must be considered in order to ensure the computational methodology used will produce accurate results and that the computational methodology is being used on the appropriate species.

Carbenes are not limited to the alkene addition reactions affording cyclopropanes presented in introductory organic chemistry classes (usually in the form of the Simmons-

Smith reaction or through the use of diazomethane with heat or light).27 The additions of carbenes to alkenes as well as the carbene’s philicity and the factors that impact it have been studied experimentally and extensively reported in the literature by researchers such 6 as Skell, Doering, Brinker, Zollinger, and Platz.28–32 These properties have also been explored theoretically by Sander, Garcia-Garibay, Moss, Perez, and Hadad.33–38

Carbenes’ unique ambiphilic nature facilitates their ability to insert into other, sometimes inert, chemical bonds as described first by Doering et al. as mentioned above.18

Intermolecular C–H insertions receive particular focus in this work and have built upon previous studies performed by Shechter, Mansoor, Liu, Platz, and Hadad to name just a few.39–43 Figure 1.4 presents a photochemical reaction that results in a C–H insertion (in this case, a 1,2-hydrogen migration). In particular, this figure highlights additional features that will be discussed at length in chapters 2 and 3.

* N2 OCH - N2 3 OCH3 H3C H3C O O

RIES

N2 H

OCH3 H OCH3 H3C O H O

Figure 1.4 A C–H insertion reaction (1,2-H migration) that was experimentally shown to bypass the typical carbene intermediate.43

While the title of this section is carbenes and ground state singlet carbenes are known to undergo these rearrangement processes, Platz et al. showed, in a number of photochemical experiments, that this particular transformation is purported to occur only in the excited state as the ultrafast time-resolved infrared (IR) spectroscopic studies revealed only the formation of the product alkene after photochemical excitation of the initial diazo and diazirine precursor.43 The alkene formed with a time constant of ~ 0.4 picoseconds, there is no apparent presence of the theoretically calculated IR marker for the singlet carbene at 1606 cm-1, and photolysis performed in a nucleophilic, singlet scavenger solvent (such as methanol-d4) all neglected to show signs of the singlet carbene.43 This was indeed an exciting result as these transformations typically do involve the carbene species. This gave further support for the implication of a concerted rearrangement in the excited state (RIES) mechanism initially proposed by Liu et. al.44 It could also be possible that for certain reactions, a mixture of traditional carbene chemistry and RIES is responsible for the relative proportions of C–H insertion products experimentally observed as in the case of Mansoor et al.40

Finally, it is worth mentioning a special class of carbenes, N-heterocyclic carbenes (NHCs),45 and their ability to catalyze synthetic transformations. In a quest to isolate a stable “bottleable” carbene, once thought to be impossible due to the sheer reactivity of these intermediates, Wanzlick et al. made a huge leap forward when they synthesized 1,3-diphenyl-2,3-dihydro-1H-imidazol-2-ylidene (1.5a) in 1960 (Figure

1.5).46

Ph Ph N N Ph Ph 2 N N N N Ph Ph 1.5a 1.5b

N N R R Cl Ph N N Ru Cl PCy3 1.5c 1.5d

Figure 1.5 Select, “famous” N-heterocyclic carbenes.

1.5a was obtained via the thermal α-elimination of chloroform from the corresponding imidazolidine. While this particular NHC was quick to dimerize (another viable bimolecular reaction available to carbenes) to 1.5b, several other transient monomeric carbenes were developed for the specific application as ligands of transition metal containing catalysts. It was not until 1991 that Arduengo and co-workers reported the first truly storable carbene, 1,3-adamantyl-2,3-dihydro-1H-imidazol-2-ylidene

(1.5c).47 With the advent of such nucleophilic and stable carbenes, many synthetically useful applications have arisen, such as olefin metathesis from organometallic catalysis utilizing the famous Grubb’s catalyst (1.5d).48 NHCs have also found new uses as more economically viable organic catalysts for condensation reactions (some enantioselective based on chiral NHC catalysts), transesterifications, acylations, ring openings, and 1,2- addition reactions.48–51 Additionally, it was reported that N-heterocyclic carbenes could 9 potentially be used to reversibly sequester carbon dioxide by Louie et al. for carbon- capture processes in the environment.52 More recently, it was shown by Falvey et al. that

NHCs may even be able to perform carbon dioxide’s photochemical reduction.53 A particular difficulty in implementing this strategy is that major sources of CO2 generation are not anhydrous environments to say the least. There are many other species present from the combustion of fuel sources like coal. These air pollutants come in the form of

NOx, SOx, as well as dust, soot, and other particulate matter. It is possible to protonate carbenes with acids as mild as water to form the corresponding carbocation, a process that has been studied with ultrafast laser spectroscopy by Scaiano et al.54

1.2.2 Radical Ions

It is important to discuss radical ions as a follow-up to carbenes due to the focus of chapter 3 of this thesis. In chapter 3, it is presented that the apparent product ratios derived from the photochemical reactions of diazo and diazirine precursors may be explained by the formation of a Rydberg excited state in which charge separation occurs between a carbene radical cation and a concomitantly formed dinitrogen radical anion, as depicted in Figure 1.6.

N N N * N N2

Figure 1.6 Depiction for the photochemical creation of a radical ion pair from a diazirine precursor via a Rydberg excited state.

This hypothesis was motivated by previous experimental work by Kropp et al. who reported that the photolysis of tetramethylethylene ((H3C)2C=C(CH3)2) in hydroxylic media showed evidence of radical ion chemistry, while in aprotic media, photolysis revealed rearrangement products consistent with those expected from C–H insertions of the corresponding tert-butyl-methylcarbene.55 This intriguing result was attributed to the photo-excitation of tetramethylethylene, promoting a π electron to an extremely diffuse s-type orbital, referred to as a Rydberg excited state, a process well described theoretically in the literature for alkenes.56,57 This excitation would allow the radical cation-like behavior that was experimentally observed by Kropp et al. Surely if the surface of the Rydberg excited state of the alkene was connected to the carbene, then the reverse could potentially be true as well. The presence of such a transient carbene radical ion intermediate (which has not been previously considered) might be able to explain the puzzling difference in product distributions between the thermolysis and photolysis of typical carbene precursors as Mansoor showed experimentally for 3-ethyl-

3-methyldiazirine (Table 1.1).40

Table 1.1 Product Distributions (%) from Photolysis and Thermolysis of 3-Ethyl-3- Methyldiazirine as a Precursor.40

Radical ions are known to undergo similar types of reactions as carbenes.8

Sigmatropic shifts of hydrides and alkyl groups on radical cation surfaces have been reported in the literature.58,59 Furthermore back electron transfer has also been reported for radical anion/radical cation pairs.60 In this case Weller and Zachariasse reported a charge-transfer reaction from the perylene radical anion to Wurster’s Blue perchlorate (a radical cation) that produces a blue chemiluminescence that is attributed to the relaxation of the singlet excited state of the perylene hydrocarbon. A side note, interesting to mention from this paper is that the authors concluded that the energy produced by the charge transfer in itself was not sufficient to produce the singlet excited sate of perylene, but instead resulted in formation of the lower energy triplet state. A process denoted as 12 triplet-triplet annihililation consisting of the collision of two triplet excited state perylene molecules yields the necessary, higher energy singlet state responsible for the lovely fluorescence.60 The first triplet excited state is calculated to be ~30 kcal/mol lower in energy than the first singlet excited state by calculations at the TD-B3LYP/6-31+G(d) level of theory, in exact agreement with the experimentally determined values from the manuscript. More important to the work in this thesis is that a back electron transfer process is not necessarily limited to a recombination to yield the closed-shell ground state of the neutral species. Radical anions have been observed to transfer electrons directly into the excited states of the corresponding species.61 Schaffner and Fischer studied the back electron transfer processes of a series of photoexcited naphthylene derivatives to cyanobenzenes by time-resolved chemically induced dynamic nuclear polarization

(CIDNP). Recombinations were found to result in mixtures of both the singlet ground state and the triplet excited states of the parent compounds.61

1.3 Overview of Chapters

Chapters 2 and 3 are intimately linked together. Chapter two covers computational studies performed in concert with ultrafast time-resolved spectroscopic studies and the steady state photochemistry of a novel diazo-containing photo precursor: ethyl 2-diazo-

3,3,3-trifluoropropanoate (CF3CN2CO2Et). Many transient species were present in the resulting ultrafast time-resolved IR spectroscopy and the computational characterization of these key intermediates using density functional theory coupled with implicit solvation models, coupled-cluster techniques, as well as quadratic configuration interaction

13 supported the assignment of key IR bands to the operational reactive intermediates as well as other observed products. This work is an extension of previous computational and ultrafast photochemical studies on an analogous compound, methyl 2-diazopropanoate

(CH3CN2CO2Me) to investigate the possibility of the experimental observation for 1,2- fluorine rearrangement that could proceed either through a relaxed singlet carbene or through rearrangement in the excited state (RIES), as shown in Figure 1.4 (vide infra).43

Chapter 3 follows directly on this theme of rearrangement in the excited state and attempts to provide computational support for a completely new hypothesized mechanism for the photochemical decomposition of nitrogenous carbene precursors. This mechanism occurs on a radical cation Rydberg-like surface. Due to computational complexity, the pure radical cation surface was investigated for several case studies including the famous ethylmethylcarbene rearrangements, as studied by Mansoor et al.40 These computations provide distinct support for the existence of the hypothesized mechanism described and for the first time are able to account semi-quantitatively for the experimental product ratios resulting from a number of diverse photochemical processes.

Chapter 4 represents collaborative work, recently submitted for peer review, performed in conjunction with the efforts of Thamattoor (Colby College), Phillips

(University of Hong Kong) and their co-workers; in this study, the computational work was done by the author of this thesis. In Chapter 4, the assignment of the transient intermediates formed upon the photolysis of 1-(1-phenylethylidene)-1a,9b-dihydro-1H- cyclopropa[l]-phenanthrene. The steady state photolysis of this species was previously reported by Thamattoor et al. to produce 1-phenylpropyne via a proposed Fritsch-

Buttenberg-Wiechell-type phenyl migration, and from a carbene intermediate.62 These results demonstrate the first experimental, spectroscopic characterization of a vinyl carbene intermediate. Density functional theory (with and without implicit solvation), complete active space self-consistent field (CASSCF) theory, and time-dependent density functional theory (TD-DFT) were employed in order to identify the transient species that evolved from the ultrafast UV-vis absorption spectra.

Chapter 5 describes a mechanistic exploration of hydrogen-atom transfer reactions. Specifically the translocation of an aryl radical to remote alkyl sites was explored through various 1,n-H-atom transfers in order to predict relative product distributions from kinetic barriers computed with density functional theory. This work was influenced by the experimental efforts of the Nagib group for remote C–H functionalization by aryl radicals as well as the original work published by Curran et al. in 1988.63 Other key reports by Baran et al. and Parasram et al. also influenced these mechanistic studies to include different moieties tethering the aryl ring to the alkyl chain targeted for remote desaturation (in this case sulfonate and silyl based tethers).64,65 The stereochemical preferences of the resulting transition states as well as the influence of electron-donating and electron-withdrawing groups on the regioselectivity of radical translocation were investigated with density functional theory.

Chapter 6 describes recently published collaborative efforts with the McGrier group investigating the mechanistic aspects of the formation of benzo-bis-oxazole-linked two-dimensional covalent organic frameworks.66 Of particular interest was mechanism of the catalytically assisted benzoxazole cyclization. Here density functional theory was

15 employed to evaluate the probability of an aerobic, radical dehydrogenation pathway proposed by Chen et al.67 This pathway seems increasingly likely when, in the case of this experimental work, catalysts were used to promote the cyclization event. It was noted computationally that the trend of cyclized product formation as well as overall COF formation seemed to correspond with good agreement with predicted bond dissociation energies. The ability of the catalyst to promote captodative assistance and stabilization was clearly observable through calculated bond dissociation energies as well through natural population analysis showing the relative delocalization of the spin density. The use of an electron deficient triazine linker as compared to a phenyl linking moiety was also observed to provide additional stabilization through a captodative effect as well as increasing radical delocalization due to favorable increased orbital overlap from overall planarization of the species.

1.4 Concluding Remarks

Overall through the judicious application of theoretical methods to these challenging problems in photochemical and mechanistic chemistry, these studies help to bring clarity to the inner workings of subtle chemical transformations. It is the duty of the computational chemist to understand what problems can and can not be addressed with current methodology and to what degree of accuracy. The increased accessibility of computing power and user-friendly interface gives the ability of performing theoretical calculations to a wider audience. Computational chemistry is a powerful tool that can be utilized, “but with great power comes great responsibility.” Anyone can build an

16 interesting molecular geometry, select some default desired options, and receive results in a relatively short amount of time. The results of such calculations can be extremely meaningful or absolutely meaningless and thus the burden falls on every user, even the most experienced, to consult the appropriate resources in order to trust the work they have done.68 In this thesis, I report a variety of computational investigations to provide synergistic understandings of a number of different experiments, either from decades ago in the extant literature or with active collaborations.

1.5 References for Chapter 1

(1) Hall, E. C. Journey to the Moon: The History of the Apollo Guidance Computer;

American Institute of Aeronautics and Astronautics: Washington DC, 1996.

(2) Bednarz, D. Minimum RAM Requirement for Facebook and Messenger Now up to

2GB. OnMSFT. October 15, 2016.

(3) Contemporary Carbene Chemistry; Moss, R. A., Doyle, M. P., Eds.; John Wiley &

Sons, Inc.: Hoboken, NJ, 2014.

(4) Platz, M. S. J. Org. Chem. 2014, 79, 2341–2353.

(5) Burdzinski, G.; Platz, M. S. J. Phys. Org. Chem. 2009, 23, 308–314.

(6) Didier, B.; Guerret, O.; François, G. P.; Bertrand, G. Chem. Rev. 2000, 39–91.

(7) Platz, M. S. Acc. Chem. Res. 1995, 28, 487–492.

(8) Reactive Intermediate Chemistry; Moss, R. A., Platz, M. S., Jones, M., J., Eds.;

John Wiley & Sons, Inc.: Hoboken, NJ, 2004.

(9) Reviews of Reactive Intermediate Chemistry; Platz, M. S., Moss, R. A., Jones, M.,

J., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007.

(10) Moss, R. A. J. Org. Chem. 2017, 82, 2307–2318.

(11) Advances in Carbene Chemistry Volume 2; Brinker, U. H., Ed.; Jai Press Inc.:

Stamford, CT, 1998.

(12) Kaur, D.; Luk, H.L.; Coldren, W. ;Srinivas, P.M.; Sridhar, L. ;Prabhakar, S. ;

Raghunathan, P.; Guru Row, T. N.; Hadad, C. M.; Platz, M. S.; Eswaran, S. V. J.

Org. Chem. 2014, 79, 1199-1205.

(13) Feng, C.; Chan, D.; Joseph, J.; Muuronen, M.; Coldren, W. H.; Dai, N.; Corrêa, I.

R.; Furche, F.; Hadad, C. M.; Spitale, R. C. Nat. Chem. Biol. 2018, 14, 276–283.

(14) McClelland, R. A. Tetrahedron 1996, 52, 6823–6858.

(15) Falvey, D. E. J. Phys. Org. Chem. 1999, 12, 589–596.

(16) Wentrup, C. Acc. Chem. Res. 2011, 44, 393–404.

(17) Nitrenes and Nitrenium Ions; Falvey, D. E., Gudmundsdottir, A. D., Eds.; John

Wiley & Sons, Inc.: Hoboken, NJ, 2013.

(18) von E. Doering, W.; Buttery, R. G.; Laughlin, R. G.; Chaudhuri, N. J. Am. Chem.

Soc. 1956, 78, 3224–3224.

(19) Moss, R. A. Acc. Chem. Res. 1980, 13, 58–64.

(20) Kadlubar, F. F. DNA Adducts of Carcinogenic Amines. In DNA Adducts

Identification and Biological Significance; Hemmink, K., Dipple, A., Shugar, D.

E. G., Kadlubar, F. F., Segerback, D., Bartsch, H., Eds.; University Press: Oxford,

UK, 1994; pp 199–216.

(21) Bunker, P. R.; Jensen, P. J. Chem. Phys. 1983, 79, 1224–1228.

(22) Gould, I. R.; Turro, N. J.; Butcher, J.; Doubleday, C.; Hacker, N. P.; Lehr, G. F.;

Moss, R. A.; Cox, D. P.; Guo, W.; Munjal, R. C.; Perez, L. A.; Fedorynski, M.

Tetrahedron 1985, 41, 1587–1600.

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Chapter 2. A Computational Study of the Photochemistry of Ethyl 2-Diazo-3,3,3- Trifluoropropanoate

2.1 Introduction

The thermal and photochemical decomposition of diazo and diazirine compounds is very diverse.1,2 Reaction pathways of these materials can lead to different functionalities: ketenes, alkenes, cyclopropanes, and other insertion products. In addition, mechanisms and intermediates can differ depending upon the source of energy used for the chemical conversion of these species, a particular highlight of the studies that follow both in this chapter and the next.3,4

The computational results presented within this chapter represent the work of the author to support IR spectral assignments and lend insight to the proposed mechanism of the photochemistry that follows. The goal is to attempt to classify the key reactive intermediates involved in these processes. The following calculations were performed in conjunction with ultrafast time-resolved infrared (TRIR) spectroscopic studies of ethyl 2- diazo-3,3,3-trifluoropropanoate (CF3CN2CO2Et) as well as steady-state photolysis product studies. While I performed the computational work described in this chapter, the project was a team effort in which the synthesis, characterization, product studies, and subsequent time-resolved spectroscopy were performed by Dr. Carolyn Reid, Dr. Hoi-

Ling (Calvin) Luk, Dr. Gotard Burdzinski, Dr. Mrinal Chakraborty, Dr. Jacek Kubicki, and Dr. Jojo Joseph and in collaboration with Professor Matthew Platz. 23

Prior studies performed by Platz et al. revealed that the photochemistry of an analogous species, methyl 2-diazopropanoate (CH3CN2CO2Me), produced methyl acrylate via expulsion of nitrogen gas and prototypical 1,2-hydrogen migration to form the corresponding alkene.5 In this case alkene formation is proposed to occur via rearrangement in the excited state (RIES),6 rather than through a traditional, thermalized carbene intermediate. Such carbenes are detectable spectroscopically and also indirectly through their capture by reaction with the solvent or other additives such as alkenes.6 As was the case for CH3CN2CO2Me, it is estimated that only one to two percent of actual carbene was formed under the photolysis conditions.

To further probe the nature of 1,2-migrations and RIES, femtosecond TRIR spectroscopy was performed in solution at ambient temperature on a novel CF3 diazo ester; specifically, can the RIES mechanism be extended to heavy atom transfer mechanisms? A summary scheme of the proposed photochemistry of CF3CN2CO2Et is provided in Figure 2.1.

ISC O O F C F3C 3 O O -N2 CHCl3

F3C CHCl2 N2 * F F Cl O RIES F C EtO 3 F O O O -N O 2 C-Cl insertion pdt

Rearrangement MeOH/CH3CN 260 nm IC excitation in CHCl3/CH3CN/MeOH CH3 C H CH O 3 N N2 N N O O O O F C F C F3C F3C 3 3 O O O O Ylide Ylide

Figure 2.1 Proposed photochemical pathways based on experimental and computational evidence.

5 In both this CF3 study and in the previous CH3 study, a methyl and ethyl ester were selected in order to give a strong IR markers as well as to prevent photochemical

Wolff Rearrangement. The Wolff Rearrangement is known to occur via the thermalized singlet carbene of a-diazoketones which has be well studied, but also can occur via rearrangement in the excited state of the precursor as shown by others as well as Platz,

Hadad and co-workers.7,8 Such rearrangements for esters are not completely without precedent, but occur predominantly in highly strained systems such as diazolactones.9

Ultrafast and steady-state photolyses were performed in chloroform, acetonitrile, and methanol due to different solvent-intermediate reactivities as well solvation effects

25 on potential intermediates. By subtle changes in the experimental spectra and comparison to calculated IR markers using different implicit solvation models, the assignments of all detected intermediates were attempted.

2.2 Computational Methodology

All calculations presented in this chapter were performed using the Gaussian ’09 suite of programs.10 A wide variety of methodologies were used to fully investigate all stationary points including the photochemical precursors, potential photoproducts, and transient reactive species. The B3LYP/6-311+G(d,p) level of theory was employed for all species with the inclusion of implicit solvation via the integral equation formalism of the polarizable continuum model (IEFPCM).11–14 Structures were modeled with implicit solvation for acetonitrile, methanol, and chloroform as well as in the gas phase. In the case of the singlet and triplet carbene intermediates, geometry optimizations and numerical frequency calculations were carried out in the gas phase at the QCISD/6-

31G(d) and CCSD/6-31G(d) levels of theory.15,16

The nature of all stationary points was verified by vibrational frequency analysis where local minima had zero imaginary frequencies and saddle points were characterized by one imaginary vibrational frequency. Transition states were confirmed to connect theoretical starting materials and products by intrinsic reaction coordinate calculations in order to follow steepest descent pathways from the saddle point to the connected minima.17

Vibrational frequencies were scaled by a factor of 0.9688. This scaling factor was reported by Radom et al. in order to account for systematic overestimation of fundamental vibrations by certain theoretical methods. This overestimation is due to multiple factors including insufficient treatment of anharmonicity, electron correlation, and basis set flexibility.18 The computed IR intensities were also normalized to the corresponding sp3 C–H stretches of the ethoxy moiety as the intensities of these stretches are expected to be invariant when going from species to species. This makes the comparison of the intensities of important IR markers such as the C=O stretching frequency more straightforward.

2.3 Results

The steady state mid-IR absorption spectrum of ethyl 2-diazo-3,3,3- trifluoropropanoate (CF3CN2CO2Et) in chloroform (CHCl3) suggests that more than one conformer must be present in the ground state. The C=N=N band is slightly asymmetrical while the C=O stretch is clearly asymmetric as seen in Figure 2.2.

This observation is supported by theory, which predicts the presence of three different conformers (Z1, E2 and Z3) in the ground state of CF3CN2CO2Et (Figure 2.3).

syn Z1 anti E2 syn Z3

Figure 2.3 Optimized geometries (B3LYP/6-311+G(d,p), CHCl3) of diazoester (CF3CN2CO2Et) conformations.

The steady state IR spectrum of the diazoester is also consistent with earlier observations of diazocarbonyl compounds, which demonstrate that these compounds exist as syn- (Z) and anti-planar (E) conformational isomers.19–22 The three low energy conformations of the diazoester (CF2CN2CO2Et) are all within approximately 1 kcal/mol of each other.

Table 2.1 Calculation of % population of diazoester conformations based on calculated free energies (B3LYP/6-311+G(d,p), CHCl3).

a Conformation ΔG298K (kcal/mol) Population (in mol %) E2 0.00 54 Z1 0.22 37 Z3 1.08 9 amol % population of different conformations are calculated assuming that X1, X2 and X3 are mutually in equilibrium with each other and so are cis and trans alkenes. Using the calculated free energy values at 298 K, equilibrium constants are calculated from the equation, ∆G = –RT lnKeq. Mol % populations are then calculated from Keq values at 298 K.

The calculated frequencies of diazo vibrations for Z1 and E2 are very similar while the C=O vibrations differ slightly. The calculated C=O and diazo vibrations of Z3 conformer are almost identical to those observed for Z1 (Figure 2.2). Thus, DFT calculations (B3LYP/6-311+G(d,p)) satisfactorily predict the experimentally observed IR vibrations of precursor (C=O and C=N=N of different conformers).

In an attempt to further investigate the state to which CF3CN2CO2Et is excited by

260 nm light, the vertical excitations for all three conformations of CF3CN2CO2Et were

29 calculated using the TD-B3LYP/6-311+G(d,p) level of theory, with consideration of implicit solvation (IEFPCM) for chloroform (Table 2.2, Table 2.3, and Table 2.4).

Table 2.2 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation Z1.

State Wavelength (nm) Oscillator Strength S1 376 0.0000 S2 259 0.0001 S3 230.4 0.0000 S4 230 0.0000 S5 220 0.4042 S6 191 0.0520 S7 184 0.0313 S8 181 0.0025 S9 179 0.0000 S10 169 0.1419

Table 2.3 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation E2.

State Wavelength (nm) Oscillator Strength S1 376 0.0000 S2 257 0.0039 S3 232 0.0001 S4 230 0.0000 S5 213 0.4442 S6 191 0.0698 S7 186 0.0402 S8 182 0.0021 S9 180 0.0001 S10 169 0.1362

Table 2.4 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CHCl3, nm) of diazoester conformation Z3.

State Wavelength (nm) Oscillator Strength S1 375 0.0000 S2 258 0.0001 S3 231 0.0010 S4 230 0.0005 S5 220 0.3978 S6 194 0.0118 S7 186 0.0651 S8 181 0.0020 S9 174 0.0002 S10 172 0.1084

The calculations suggest that 262 nm light would correspond to excitation to the

S2 state for conformation Z1 and E2 with non-zero oscillator strength, while for Z3, this excitation corresponds to a dark state with the oscillator strength being zero.

Additionally, the oscillator strength of the Z1 conformer is much lower than that of E2.

Therefore, theory predicts that only the anti (E2) conformer will be excited. Thus according to the Kaplan, Meloy, and Mitchell (KMM) rule, it is reasonable to expect that the ketene will be not produced directly from the excited state of the diazo compound.20,21,23

TRIR transient spectra in the spectral range 2050 – 2160 cm-1 are presented in

Figure 2.4a. An absorption band for the ketene (C=C=O vibration), if any is produced, would be expected in this region. The shape of time-resolved spectrum recoded at 113 ps, after the laser pulse and after all spectral changes are complete, has the same shape as the

31 normalized steady-state, pre-photolysis FTIR spectrum. Therefore, there is no evidence that the ketene is formed under these experimental conditions. The only spectral changes observed are due to fast internal conversion (IC) from some higher lying Sn state to the S0 state. The vibrationally hot ground state is populated very efficiently, in less than 1 ps.

Due to fast internal conversion (IC), there are observed spectral changes typical of vibrational cooling (VC) of the repopulated ground state that are visible up to ~ 70 ps.24

The recovery of the C=N=N vibration may be used to calculate the quantum yield of ground state recovery, i.e. IC. In CHCl3, the quantum yield of IC is equal to 0.56 (Figure

2.4b).

The spectrum recorded in the range 1725 – 1615 cm-1 is shown in Figure 2.5. The spectral evolution observed in this range is quite complicated, as many species may contribute: the hot ground state of precursor, hot nascent singlet carbene, relaxed singlet carbene, and finally the triplet carbene. Steady state photolysis studies clearly show that the diazirine is formed during the photolysis by the appearance of a characteristic shorter wavelength absorption band in the UV-vis spectral range (Figure 2.6).

Figure 2.5 TRIR spectra recorded for CF3CN2CO2Et in chloroform upon excitation with the 260 nm light. The time delays for (a) and (b) are the same. Also, the time delays for (c) and (d) are the same. The normalized FTIR spectra are shown as dotted lines.

0.4

Prephotolysis 2 min 0.3 4 min 7 min

0.2 Abs

0.1

0.0

300 350 400 450 Wavelength / nm Figure 2.6 Steady state UV-vis photolysis of CF3CN2CO2Et in CHCl3 (OD=0.89 at 266 nm) with 260 nm light.

It is therefore concluded that the IR in the region of 1725 – 1615 cm-1 will be further convoluted by the presence of the diazirine stretching frequency (a hot ground state and thermalized diazirine). Additionally, theory predicts that the diazirine is expected to exist as a mixture of three rotamers in solution at room temperature (Figure

2.7).

syn Z1 anti E2 syn Z3

Figure 2.7 Optimized geometries (B3LYP/6-311+G(d,p), CHCl3) of diazirine (CF3CN2CO2Et) conformations.

The vibrations of all different species are predicted by theory: singlet carbene, triplet carbene, diazoester, diazirine, chloroform C–Cl insertion product, 1,2-fluorine migration product, methanol ylide, and acetonitrile ylide). The calculated energies of the three diazirine conformations and IR frequencies are given in Table 2.5.

Table 2.5 Calculation of percentage population of diazirine conformations based on calculated free energies in chloroform.

a Conformation ΔG298K (kcal/mol) Population (in mol %) Z1 0.00 57 E2 0.44 27 Z3 0.77 15 amol % population of different conformations are calculated assuming that X1, X2 and X3 are mutually in equilibrium with each other and so are cis and trans alkenes. Using the calculated free energy values at 298 K, equilibrium constants are calculated from the equation, ∆G = –RT lnKeq. Mol % populations are then calculated from Keq values at 298 K.

The contributions of a given species to the signal detected are marked in Figure

2.5. As the amplitudes of positive bands detected in the spectral range 1725 – 1620 cm-1

35 are very weak, and many species contribute in the same spectral range, it is not possible to obtain an accurate fit. Based on the spectral changes observed, however, the time constants maybe estimated.

Just after the laser pulse, a negative band at ~ 1720 cm-1 (C=O vibration) due to bleaching of the ground state of the precursor, is present (Figure 2.5b). A wide positive band is also observed in the spectral range 1700 –1620 cm-1. As the ground state of the precursor is already established from the diazo band (Figure 2.4), a species clearly contributing to this spectral range is the hot ground state of the precursor.

A few picoseconds after the laser pulse, a positive band rises at 1625 cm-1 (Figure

2.5b,d). At 17 ps after the laser pulse, this band shifts and reaches a maximum that is located at 1630 cm-1. The band starts to decay together with further thermalization – the maximum of this band moves from 1630 cm-1 at 17 ps to 1645 cm-1 at 65 ps. This band may be assigned to singlet carbene as theory predicts the C=O stretch of singlet carbene at 1621 cm-1. As the singlet carbene decays with a time constant of about 80 ± 20 ps, a new band with a maximum at the 1682 cm-1 rises with the same time constant. The carrier of this band is not persistent, as it was not detected during steady state photolysis

(Figure 2.8).

Based on this evidence and based on a diagnostic experiment in MeOD (vide infra), this band was assigned to the triplet carbene. DFT calculations predict the carbonyl stretching frequencies for the singlet and triplet carbene in implicit chloroform at 1620 cm-1 and 1614 cm-1, respectively, in opposite order of what is assigned based on the ultrafast data. With such a tight splitting in predicted stretching frequencies, it is difficult to assign which signals belong to which species based on this computational method. In order to evaluate these frequencies at different levels of theory, CCSD/6-

31G(d) and QCISD/6-31G(d) calculations were performed. These gas-phase calculations revealed singlet carbonyl stretching frequencies at 1619 and 1650 cm-1 for QCISD and

CCSD, respectively. Triplet carbonyl frequencies are predicted at 1691 cm-1 and 1686 cm-1 for the QCISD and CCSD levels of theory, respectively. These reveal a larger gap between the singlet and triplet carbonyl stretching frequencies and are more closely in line with the experimental results.

The positive weak absorption band at about 1750 cm-1 is present immediately (< 1 ps) after the laser pulse. A bi-exponential function describes the kinetics recorded at 1750 cm-1 (Figure 2.9d). The peak rising with a time constant of 10 ± 6 ps could be assigned to

VC of the hot nascent diazirine (present within 1 ps of the laser pulse), formed via the excited state of precursor (RIES). However, the slow rise (122 ± 44 ps) at 1750 cm-1 is due to an intermolecular reaction (C–Cl insertion) of the thermalized singlet carbene which decays with a time constant of 80 ± 20 ps. Calculations predict that the C–Cl insertion product has an IR active marker at 1740 cm-1. Unfortunately, the clear rise of a diazirine band could not be observed in CHCl3 due to the C–Cl insertion product

38 formation dominating this spectral region. We believe that two IR bands with maxima at

1745 cm-1 and 1779 cm-1, recorded during steady state photolysis can be assigned to the

C–Cl insertion product (C=O stretch) and diazirine formation (also C=O stretch) as shown in Figure 2.8. The less intense C–N=N–C ring vibration of the diazirine must be buried under these more intense IR bands. However, the accuracy of the calculated IR markers (1740 cm-1, C=O vibration of C–Cl insertion product; 1704 cm-1, C=O vibration of diazirine) with experimentally observed ones (the 1745 cm-1 and the 1779 cm-1) is rather poor.

Figure 2.9 Diazirine and C–Cl insertion product formation upon photolysis of CF3CN2CO2Et in CHCl3 with 260 nm light for (a) delays up to 78 ps and (b) for delays longer than 78 ps. Normalized FTIR spectra of CF3CN2CO2Et are shown as dotted lines. (c) Kinetics recorded at 1720 cm-1 (the recovery of the ground state) and (d) kinetics recorded at 1750 cm-1 (diazirine and C–Cl insertion product formation).

Previous studies showed that the conjugated alkene has an IR active band near

1750 cm-1.5 However, in this work it has been confirmed by steady-state product analysis that no alkene is formed during the photolysis of CF3CN2CO2Et under the conditions of our experiments. Alkene formation via thermalized singlet carbene was also excluded based on a very high computed energy barrier (21 kcal/mol) for this process (Figure

2.10).

T.S of 1,2-F sﬁft E = 21 (kcal/mol)

singlet E = 54

Energy (kcal/mole) Energy carbene (kcal/mole)

s-trans alkene

Reaction Coordinate

Figure 2.10 Transition state of 1,2-F shift of CF3CN2CO2Et (B3LYP/6-311+G(d,p))

In this experiment the diazirine was produced instead of the alkene. A diazirine ring vibration and a relatively more intense carbonyl stretch are computationally

40 predicted for the three diazirine conformers at frequencies of about 1730 cm-1 and 1704 cm-1, respectively (Z1, E2, and Z3).

TRIR experiments were repeated in acetonitrile (MeCN) in order to validate the above results. In acetonitrile, the E2 diazo conformer is the most stable in the ground state

(E2 68%, Z1 27% and Z3 5%); additionally, it has the highest calculated oscillator strength around the experimental photolysis wavelength at around 260 nm (E2 0.0055, Z1 0.0002 and Z3 0.0003; Table 2.7, Table 2.8, and Table 2.9).

Table 2.6 Calculation of % population of diazoester conformations based on calculated free energies in acetonitrile.

a Conformations ΔG298K (kcal/mol) Population (in mol %) E2 0.00 68 Z1 0.55 27 Z3 1.46 5 amol % population of different conformations are calculated assuming that X1, X2 and X3 are mutually in equilibrium with each other and so are cis and trans alkenes. Using the calculated free energy values at 298 K, equilibrium constants are calculated from the equation, ∆G = –RT lnKeq. Mol % populations are then calculated from Keq values at 298 K.

Table 2.7 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine conformation Z1 in acetonitrile.

State Wavelength (nm) Oscillator Strength S1 296 0.0004 S2 269 0.0003 S3 234 0.0018 S4 214 0.0003 S5 193 0.0010 S6 186 0.0004 S7 178 0.3769 S8 172 0.0315 S9 171 0.0058 S10 169 0.0017

Table 2.8 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine conformation E2 in acetonitrile.

State Wavelength (nm) Oscillator Strength S1 297 0.0002 S2 266 0.0005 S3 238 0.0146 S4 219 0.0002 S5 196 0.0004 S6 189 0.0041 S7 180 0.2071 S8 174 0.0031 S9 171 0.1187 S10 167 0.0011

Table 2.9 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), nm) of diazirine Z3 conformer in acetonitrile.

State Wavelength (nm) Oscillator Strength S1 296 0.0004 S2 268 0.0004 S3 235 0.0021 S4 213 0.0004 S5 202 0.0003 S6 182 0.0028 S7 178 0.3299 S8 173 0.0983 S9 170 0.0056 S10 167 0.0038

Therefore, theory predicts that mostly the anti (E2) conformer will be excited, a result consistent with the calculations performed in CHCl3. Steady-state and time- resolved data are presented in Figure 2.11 and Figure 2.12. In MeCN, similar spectral evolutions were observed to those presented in CHCl3 with the exception that the IR band of the acetonitrile ylide was observed at about 1670 cm-1 (Figure 2.12c,d). This ylide was observed in lieu of the triplet carbene band detected in CHCl3. Calculations for the acetonitrile ylide predict an intense IR marker at 1615 cm-1 attributed to the carbonyl stretching frequency. This is noticeably lower than the predicted stretching frequencies for the diazirine ring and the carbonyl of the diazirine containing species and corresponds with the trends observed in both the steady state photolysis and in the TRIR (Figures 2.11 and 2.12, respectively).

Figure 2.11 Steady state photolysis of CF3CN2CO2Et in MeCN (a) The decay of precursor monitored on C=N2 vibration. (b) Spectral changes observed in the spectral range of C=O vibration (decay of C=O vibration of precursor and alkene formation). (c) Precursor consumption vs. time of irradiation. (d) FTIR difference spectra. Difference FTIR for given time of irradiation was calculated as the difference between spectrum after irradiation minus scaled FTIR prior irradiation. Scaling factors were calculated based on precursor consumption taken from plot (c). (e) Relative efficiency of products formation vs. precursor consumption.

We believe that one of the photoproducts formed during the irradiation of the diazo precursor under our experimental conditions is the diazirine which interconverts from the diazo precursor. In acetonitrile, the diazirine species is predicted to have strong

-1 -1 carbonyl vibrations at about 1695 cm (E2 1694, Z1 1697, and Z3 1697 cm ) and a relatively weak vibration of attributed to the diazirine ring at about 1730 cm-1 (calculated at 1731, 1726, and 1726 cm-1) for the respective conformers listed above. FTIR spectra recorded after steady state photolysis also shows two IR markers in the spectral range of our interest: one at the 1672 cm-1 and the second at the 1751 cm-1 (Figure 2.11b,d). The

1672 cm-1 band may be assigned to the C=O stretch, while the 1751 cm-1 band is attributed to the C–N=N–C ring vibration of the diazirine. Experimentally observed amplitudes agree well with calculated intensities.

It is possible that one of the calculated diazirine bands (1694 – 1697 cm-1) may overlap with the experimentally observed acetonitrile ylide band (1670 cm-1) on the ultrafast time scale. However, the C–N=N–C ring vibration of diazirine is predicted to be located at about 1726–1731 cm-1 and is underestimated by 25 cm-1 from the experimentally observed one (1750 cm-1). The positive absorption band at about 1750 cm-1 is present immediately (< 1 ps) after the laser pulse and spectral changes are not observed after 50 ps after the laser pulse due to VC of the nascent diazirine (Figure

2.12e,f). As an assignment based on calculated IR markers is not straightforward, the formation of the diazirine in MeCN was additionally confirmed by the rise of a shorter- wavelength absorption band in UV-vis spectral range during steady state irradiation

(Figure 2.13). The presence of diazirine was also confirmed by product studies.

0.5

Prephotolysis 0.4 2 min 4 min 6 min 0.3 9 min 12 min 18 min Abs 0.2

0.1

0.0

250 300 350 400 450 Wavenlength / nm Figure 2.13 Steady state UV-vis photolysis of CF3CN2CO2Et in MeCN (OD=0.85 @266 nm) with 260 nm light.

In order to additionally test the assignment of the 1682 cm-1 band to the triplet carbene (Figure 2.5d), a control experiment was performed in MeOD, an excellent singlet carbene scavenger. The transient spectra recorded with 260 nm excitation in MeOD are shown in Figure 2.14.

Figure 2.14 TRIR spectra recorded for CF3CN2CO2Et in MeOD upon excitation with the 260 nm light for different times of delay (a-c). The transient band at 1618 cm-1 is assigned to the alcohol ylide.

A band with a maximum at 1630 cm-1 (thermalized singlet carbene) detected in

-1 CHCl3 is not visible in MeOD. Instead, a band with a maximum at 1618 cm is formed.

Initially a wide positive signal is detected (either hot singlet carbene or hot alcohol ylide).

The band with the maximum at the 1618 cm-1 may be assigned as the alcohol ylide.25

Theory predicts the IR marker for the MeOH ylide at 1648 cm-1. The ylide decays with a time constant of 150 ps (Figure 2.15).

-1 -6 1618 cm 500x10 A1 =-0.00045 ± 0.00020 400 t1 =28 ± 16 ps A2 =0.0005 ± 0.0002 300 t2 =150 ± 30 ps A offset =0.00017 ± 0.00003 D

200

100

0 0 200 400 600 800 1000 time delay / ps Figure 2.15 Photolysis of CF3CN2CO2Et in MeOD (lexc=260 nm). Kinetics recorded at 1618 cm-1. Alcohol-ylide formation and decay.

The absence of the 1630 cm-1 band (singlet carbene) means that hot singlet carbene was very efficiently scavenged by methanol and that the alcohol ylide was formed instead. The formation of the diazirine band (Figure 2.16) was also observed in MeOD.

The 1750 cm-1 band appears just after the laser pulse, undergoes VC, and its formation is complete within ~ 30 ps. No spectral changes after ~ 30 ps are visible. We believe that in MeOD, diazirine is formed by RIES and the slow time rise is due to VC of the nascent diazirine.

-1 Therefore, the band formed at the 1682 cm in CHCl3 (2.5d) may be assigned to the triplet carbene. The diazo vibration spectral range was also monitored in MeOH and, as in CHCl3, no trace of ketene was detected (Figure 2.17).

Figure 2.17 TRIR spectra recorded for CF3CN2CO2Et in MeOH upon excitation with the 260 nm light (recovery of diazo stretch). Normalized FTIR spectra of CF3CN2CO2Et in MeOH are shown as dotted lines.

Based on the recovery of the diazo vibration, the quantum yield of IC is equal to

0.61 in MeOH (Figure 2.18). Thus, a similar fraction of excited molecules underwent photochemistry in the solvents used: 44% in CHCl3, 45% in MeCN and 39% in MeOH.

0.0

-0.2

-0.4

-0.6 -3 2137 cm-1 x10 -0.8 A = -0.00084 ± 0.00002 -1.0 t = 14.2 ± 1.0 ps A¥ = -0.000516 ± 0.000010 -1.2

-1.4

0 200 400 600 800 1000 time delay / ps Figure 2.18 Photolysis of CF3CN2CO2Et in MeOH (lexc=260 nm). Kinetics recorded at 2137 cm-1in MeOH (the recovery of the ground state of precursor) with the fit of one- exponential function: (FIC=A1/(A1+offset)=0.61).

The triplet carbene is found to be more stable than the singlet carbene by about 3 kcal/mol. The triplet carbene is treated as an open-shell intermediate during DFT calculations. The transition state (TS) for the 1,2-F shift from the singlet carbene was successfully located and verified by frequency calculation in the gas phase with an identical basis set and level of theory. An IRC search performed on the located TS shows that the calculated stationary point indeed connects the singlet carbene and the s-trans conformation of the product alkene (Figure 2.10) which can easily equilibrate to the s-cis conformation, as stated earlier. The calculated activation barrier for 1,2-F shift is found to be 21 kcal/mol in the gas phase (Figure 2.10). This value is in excellent agreement with both experimental and previous computational values of 1,2-F migrations (QCISD(T)–

FC/6-311(2d,2p)//MP2FC/6–31G(d,p) with a value of 21.5 kcal/mol).26,27

2.4 Conclusions

The photochemistry of ethyl 2-diazo-3,3,3-trifluoropropanoate was studied extensively by both experimental and computational means in a variety of solvents.

Expected 1,2-fluorine migration was not observed and no alkene product was formed despite the presence of singlet carbene post-photolysis. Authentic alkene was synthesized and post-photolysis mixtures were separated by GC-MS; however, no peaks with similar retention times or MS traces were present in the mixture that corresponded to the authentic alkene. The absence of alkene formation also excludes the potential of the rearrangement in the excited state pathway which was clearly the case in the previous photolysis studies of methyl 2-diazopropanoate.5

Other carbene chemistry was observed in the form of insertion products resulting from the reaction of the reactive carbene intermediate with the solvent. Comparison to theoretically calculated IR frequencies and vertical excitations allowed for identification of experimental, transient IR bands as well as steady state photolysis studies characterized with IR and UV-vis spectroscopy. The major isolable photoproduct was a result of the isomerization of the diazo functionality to the diazirine which was confirmed by steady state photolysis and UV-vis measurements. Photoisomerization of diazo compounds to diazirines is reported in the literature and is seen in cases like the photolysis and interconversion of diazo Meldrum’s Acid to its diazirine counterpart.9,28 In the case where Wolff Rearrangement does not occur, the other major observable product was the diazirine as concluded separately by Platz and Popik.9,28 It is reasonable to conclude in this case that an appreciable amount of observable product formation contains the diazirine moiety as other photochemical pathways are not evident. In this case the formation of diazirine during ultrafast experiments served to as another complicating factor spectral identification of active intermediates.

2.5 References for Chapter 2

(1) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577–6605.

(2) Moss, R. A. Acc. Chem. Res 2006, 39, 267–272.

(3) Mansoor, A. M.; Stevens, I. D. R. Tetrahedron Lett. 1966, 7, 1733–1737.

(4) Chang, K. T.; Shechter, H. J. Am. Chem. Soc. 1979, 101, 5082–5084.

(5) Burdzinski, G.; Zhang, Y.; Selvaraj, P.; Sliwa, M.; Platz, M. S. J. Am. Chem. Soc. 53

2010, 132, 2126–2127.

(6) Bonneau, R.; Liu, M. T. H.; Kim, K. C.; Goodman, J. L. J. Am. Chem. Soc. 1996,

118, 3829–3837.

(7) Kirmse, W. European J. Org. Chem. 2002, 2002, 2193.

(8) Burdzinski, G.; Kubicki, J.; Sliwa, M.; Réhault, J.; Zhang, Y.; Vyas, S.; Luk, H.

L.; Hadad, C. M.; Platz, M. S. J. Org. Chem. 2013, 78, 2026–2032.

(9) Burdzinski, G.; Réhault, J.; Wang, J.; Platz, M. S. J. Phys. Chem. A 2008, 112,

10108–10112.

(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;

Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;

Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;

Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;

Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,

T.; Montgomery, J. A., Jr.; Pe, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;

Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,

S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;

Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;

Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;

Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;

Dapprich, S.; Daniels, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,

Revision E. 01. Gaussian, Inc.: Wallingford CT, 2009.

(11) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.

(12) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.

(13) Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984, 80, 3265–3269.

(14) Tomasi, J.; Mennucci, B.; Cancès, E. J. Mol. Struct. THEOCHEM 1999, 464, 211–

226.

(15) Pople, J. A.; Head-Gordon, M.; Raghavachari, K. J. Chem. Phys. 1987, 87, 5968–

5975.

(16) Bartlett, R. J.; Purvis, G. D. Int. J. Quantum Chem. 1978, 14, 561–581.

(17) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368.

(18) Merrick, J. P.; Moran, D.; Radom, L. J. Phys. Chem. A 2007, 111, 11683–11700.

(19) Curci, R.; Difuria, F.; Lucchini, V. Spectrosc. Lett. 1974, 7, 211–218.

(20) Kaplan, F.; Meloy, G. K. Tetrahedron Lett. 1964, 5, 2427–2430.

(21) Kaplan, F.; Meloy, G. K. J. Am. Chem. Soc. 1966, 88, 950–956.

(22) Bogdanova, A.; Popik, V. V. J. Am. Chem. Soc. 2004, 126, 11293–11302.

(23) Kaplan, F.; Mitchell, M. L. Tetrahedron Lett. 1979, 20, 759–762.

(24) Hamm, P.; Ohline, S. M.; Zinth, W. J. Chem. Phys. 1998, 106, 519–529.

(25) Xue, J.; Luk, H. L.; Platz, M. S. J. Am. Chem. Soc. 2011, 133, 1763–1765.

(26) Holmes, B. E.; Rakestraw, D. J. J. Phys. Chem 1992, 96, 2210–2216.

(27) O’Gara, J. E.; Dailey, W. P. J. Am. Chem. Soc. 1994, 116, 12016–12021.

(28) Bogdanova, A.; Popik, V. V. J. Am. Chem. Soc. 2003, 125, 14153–14162.

Chapter 3. A Closer Look at Rearrangement in the Excited State of Nitrogenous Carbene Precursors: Radical Cation-like Behavior?

3.1 Introduction

The intramolecular reactions of carbenes are some of the most extensively studied in reactive intermediate chemistry. Over the years, carbenes as reactive intermediates have been characterized by spectroscopic techniques, including matrix isolation in the

1960s and nanosecond laser flash photolysis in the 1980s.1–4 With the advent of ultrafast femtosecond (fs) time-resolved spectroscopic techniques, scientists began to provide indirect and dynamic visualization of these fleeting species at ambient temperature.5,6 The mechanisms by which these intermediates form and react are of significant importance to the physical organic chemist that wishes to understand the delicate, and sometimes both beautiful and complicated, fundamental processes of the chemical world. Attempting to define the landscape of these transformations can help enable all chemists to wield these powerful tools in order to incorporate meaningful functionality into molecular scaffolds with surgical precision.

Traditional nitrogenous precursors to carbenes, particularly diazo and diazirine moieties, impart their own subtle complexities to the available chemistry. For this reason, as well as for safety considerations, synthetic chemists sometimes forgo the use of diazirine and diazo compounds and instead use metal carbenoid species or haloform/base combinations in order to produce the desired species in situ. The Simmons-Smith 56 reaction was published in 1958 and since then, a number of modifications have improved and tuned the reaction for specific stereochemical outcomes.7 In particular, Shi et al. proposed an asymmetric Simmons-Smith cyclopropanation of an unfunctionalized alkene using a commercially available dipeptide as a chiral auxiliary (Figure 3.1).8

O CO2Me BocHN N

R1 1 R ZnEt2, CH2I2 R3 3 2 R CH2Cl2 R R2 H

Figure 3.1 Shi’s asymmetric Simmons-Smith modification.8

The reactivity of a simple compound, 3-ethyl-3-methyldiazirine (EMD), is quite astonishing. First reported by Mansoor and Stevens in 1966, there is a distinct bifurcation in the product ratios depending upon whether the diazirine precursor is thermalized or converted photochemically with UV radiation (Table 3.1).9

Table 3.1 Product Distributions (%) from Photolysis and Thermolysis of 3-Ethyl-3- Methyldiazirine as a Precursor.9

These results have been the object of debate since its publication and have received extensive study by many investigators including Liu and Bonneau who coined the phrase “rearrangement in the excited state” (RIES).10 Mansoor and Stevens postulated back in 1966 that the observed photochemical product distribution was due to a hot– radical effect of a vibrationally hot carbene derived from the concentrated stimulation of the diazirine precursor by highly energetic light. This vibrationally hot, excited carbene species then undergoes various intramolecular insertion reactions in different ratios then the relaxed carbene produced by thermolysis of the diazirine.

This peculiar photochemical reactivity is not limited to just 3-ethyl-3- methyldiazirine (EMD) but has also been reported (but not limited) to occur in 58 compounds 3.2a, 3.2b, and 3.2c by Mansoor, compound 3.2d by Shechter et al., as well as in 3.2e which was recently studied by Platz and Hadad (Figure 3.2).9,11

N N N N N N H

3.3a 3.3b 3.3c N N N 2

3.3d 3.3e

Figure 3.2 Examples of nitrogenous precursors that yield different product results upon thermolysis and photolysis.

The major focus of this chapter will be upon the results concerning 3-ethyl-3- methylcarbene (EMC); however, theoretical work on 3.2d and 3.3e will also be discussed.

The explanation behind the insertion products arising from nitrogenous precursors is certainly “a tale that has grown in the telling.”12 In particular, the results of pyrolysis and photolysis of EMD along with the corresponding mechanism of action has been puzzled over since its first report in 1966.9 With ultrafast techniques, and other photochemical studies, the prototypical products of nitrogenous carbene precursors have been observed. The typical reactions result in ketenes from the Wolff Rearrangement as well as intramolecular (C–H, C–C, and C–X) insertion reactions.13,14 However, despite 59 the presence of these products, under certain conditions no actual carbene intermediate is observed or trapped! It is apparent that the RIES pathway bypasses the traditional carbene route that was initially expected.

The stereochemical outcomes from the photolysis of some alkylchloro diazirine species have been noted in the literature as part of a broader probe into the effect of RIES and rearrangements that occur in the presence of alkenes. In this way the rates of intermolecular vs intramolecular reactions of carbene compounds were assesed.10 While carbenes are generally known to react with alkenes, especially tetramethylethylene

(TME), photolysis of n-propylchlorodiazirine in the presence of TME shows intramolecular insertion and rearrangement products in addition to the intermolecular reaction producing the predicted cyclopropyl derivative.10 Bonneau et al. posited that if one considers the simplest case of two branching pathways, i.e., one leading to cyclopropanation and the other to alkene formation (Figure 3.3), then the ratios of these products should be linear with respect to the concentration of the alkene. However, at large concentrations of the alkene, the concentration of rearranged products exceeds expectations producing a nonlinear curve. Such a result is explained either by a RIES or carbene-alkene complex mechanism in which the alkene stabilizes the carbene through a contact pair relationship.10

+ N2 N N * TME Cl Cl Cl Cl Cl Cl

h! ∆

N N Cl Cl Cl Cl

Figure 3.3 Rearrangement vs intramolecular reaction of chloromethyl-chlorocarbene (CMCC).

The cis-1,2-dichloroethene product is displayed in Figure 3.3 as it is the major photolysis product derived from chloromethyl-chlorodiazirine; the rearrangement process yields an ~ 4:1 ratio of the cis:trans alkenes while pyrolysis yields a 9:1 ratio.10 In the case of the photolysis of benzylchlorodiazirine, the result is the exact opposite with the trans product being favored by a 3:1 ratio.15 The pyrolysis of benzylchlorodiazirine shifts this ratio to 8:1.16 Bonneau and Liu noted this as an interesting result with no readily apparent, conclusive answer.10,17 It is further elaborated in the article, and more concisely stated in Volume 2 of Bonneau and Liu’s article in Advances in Carbene Chemistry chapter one, that the efficiency of the RIES process was evaluated to be greater for chloromethyl-chlorocarbene than for benzylchlorodiazirine.17 This result, accompanied by the assertion of the non-negligible effect of quantum mechanical tunneling, will be explored computationally for these systems.

The thermal product distribution of many carbene insertion reactions can be readily predicted by computational techniques as previously demonstrated by Sulzbach et al.18 In particular, Sulzbach et al. studied the thermal products derived from ethylmethylcarbene and utilized the BHandHLYP hybrid density functional (as implemented by Gaussian ’94).19 This functional uses a mixture of exact Hartree-Fock exchange and Becke’s density functional exchange, but is unique and different than the

“half and half” functionals described by Becke himself.20 The results of the BHandHLYP calculations will be presented for comparison along with more recent calculations that are the focus of this chapter.

To further investigate the rearrangement mechanism and to see if the product distribution for the photolysis of EMD could be theoretically predicted, Luk et al. performed a rigorous evaluation of the diazirine/carbene system using complete active space self-consistent field theory (CASSCF) as well as the coupling of the CASSCF wavefunction with 2nd order Møller-Plesset perturbation theory (CASPT2) as implemented in the Molcas 7.4 suite of programs.21 Coupled cluster theory with a full treatment of single and double excitations as well as the estimation of triples contribution

(CCSD(T)) and CASPT2 are considered to be gold standards in computational chemistry with respect to accuracy. CASPT2 has the advantage of addressing both dynamical and non-dynamical correlation by the use of a multi-reference wavefunction coupled with perturbation theory. CASSCF has the benefit of non-dynamical correlation which can account for the fact that some molecules are only properly described with more than one degenerate or nearly-degenerate determinant (or electronic configuration).22 Carbenes,

62 nitrenes, and nitrenium ions are all examples of species that sometimes require a multireference wavefunction to properly describe their properties. Second-order Møller-Plesset perturbation theory (MP2) helps to account for dynamical correlation or the movement of electrons and electron–electron repulsion. CASSCF and CASPT2 calculations must be performed with diligence as the chemist must select an appropriate number of electrons and an “active space” of orbitals in order to mix and generate all possible configurational state functions (CSFs). This electron orbital selection is often depicted as CAS(m,n) where m and n are the number of electrons and orbitals respectively. Ideally, one would want to include all of the valence electrons/orbitals of the molecule as these are most likely to be involved in chemistry; however, this is sometimes impossible due to the computational cost. The current release of Gaussian ’16 states that active spaces including up to 16 orbitals are feasible.23 An example of the number of singlet configurations (N) that can be generated from a combination of m elections in n orbitals would be described by the following equation 3.1.22

�!(��)! � = � � � � (3.1) ! �!� !� �! � � � �

The number of CSFs increases dramatically with the number of orbitals. A singlet

CAS(2e,2o) calculation would have 4 total CSFs or 3 unique CSFs (Figure 3.4), while

CAS(12e,10o) calculations, like those previously performed on the singlet state of

EMD,24 would consist of 13,860 unique CSFs. Each CSF undergoes its own iteration of optimizations before the final wavefunction is produced and optimized. 63

This process describes one complete cycle of optimization for a given set of atomic coordinates, but the process must be repeated multiple times as the computational programs attempt to find the requested geometric stationary point. These calculations require both a large amount of memory to store the necessary integrals and then usually a large number of CPU cycles to reach a converged solution.

With CASSCF, it was possible to evaluate the energetics of the open-shell singlet, excited S1 state of EMC and its decay pathways to the S0 ground state. This was done by simultaneously tracing and optimizing the S1 and S0 potential energy surfaces to approach a geometric point at which the surfaces cross (referred to as a conical intersection).25 An explanation for the increased amount of 1-butene under photochemical conditions is rationalized by the comparison of the energetics for the conical intersection (CI) leading to 1-butene as opposed to methylcyclopropane, with 1-butene being energetically preferred. The CI located for the formation of trans-2-butene from the S1 state was found to be only slightly lower in energy than the CI for 1-butene formation which is also 64 consistent with the photolysis results.24 CASSCF, CASPT2, and resolution-of-identity, second-order coupled-cluster theory (RI-CC2) calculations performed by Luk et al.24 also reproduced thermal product distributions that were well in agreement with the previous results by Sulzbach et al.18

To summarize, thus far the possible sources for the apparent product distribution from the photolysis of EMD are already quite diverse. There exists the possibility to produce rearrangement products from a traditional thermalized carbene after release of nitrogen, a contribution from the S1 open-shell singlet excited carbene that decays through various surface crossings to the products, vibrationally hot versions of these pathways, and finally a concomitant rearrangement with expulsion of nitrogen gas in the excited state of the diazirine (Figure 3.5). A theoretical treatment giving a more quantitative view of the formation of isobutene has not yet been realized. These factors have motivated the following work.

RIES

N2 H3C * H C H3C N 3 H CH C N 3 2 H3CH2C H3CH2C

* H3C

H3CH2C

H3C

H3C N H3CH2C N H3CH2C

Paul Kropp and Edward Reardon reported in JACS in 1971 that photolysis of tetramethylethylene in alcohol solvents leads to radical cation-like behavior based upon multiple experiments and product studies (Figure 3.6).26

hν ROH

ROH H

H OR

-H H -H H

OR OR

Figure 3.6 Proposed pathway for observed product formation in hydroxylic media.26

In addition, the photolysis of tetramethylethylene in aprotic solvents slowly leads to rearranged products, some of which are consistent with the species obtained from the rearrangement of a carbene (tert-butyl-methylcarbene, Figure 3.7).

253.7 nm + + C6H12

Figure 3.7 Photolysis of TME yields rearranged products.26

Kropp and co-workers suggested that this radical cation pathway is not the result of complete ionization of tetramethylethylene which occurs at 8.30 eV as the experimental photolysis conditions only provide 4.88 eV. Instead, they proposed that the first singlet excited state of tetramethylethylene corresponds to the promotion of a π electron to an extremely diffuse orbital, referred to as a Rydberg excited state,27,28 yielding radical cation–like behavior. The π®R(3s) transition and π®π* transitions are nearly overlapping in required absorption energy, but both have been experimentally identified for ethylene and its alkylated derivatives.29 These states can also be calculated and observed with various theoretical methods.30

Thus, if the potential energy surface connecting the Rydberg excited state can lead to carbene-like products, then this radical cation like pathway may possibly explain some of the photochemical products observed experimentally. Hence, we hypothesize that in the particular case of diazirines and diazo compounds (which can interconvert photochemically), initial photochemical excitation of a nitrogenous precursor could lead to an excited state in which, as nitrogen is expelled, formation of a Rydberg excited state in which charge separation occurs between a carbene radical cation and a concomitantly formed dinitrogen radical anion (Figure 3.8).31

N N N * N N2

Figure 3.8 Depiction for the photochemical creation of a radical ion pair from a diazirine precursor via a Rydberg excited state.

Such a radical ion pair may collapse to regenerate the ground state precursor

(perhaps thermally excited), may lead to diazirine to diazo interconversion, may lead to typical carbene-like migration products, may form the triplet carbene, or may generate the open or closed-shell singlet carbene upon back electron transfer to the radical cationic

“carbene” from the dinitrogen radical anion. If this back electron transfer occurs, it would be expected that the product distributions will be impacted by open-shell and closed-shell carbene chemical pathways and mechanisms. We will explore the role of the carbene radical cation structures to generate distinctive aspects of the final product distributions.

3.2 Computational Methods

A wide variety of computational methods were applied to multiple species to provide the following data. All calculations were performed using the Gaussian ’16 suite of programs.32 Geometry optimizations and vibrational frequency calculations for EMC and its corresponding radical cation where performed at the B3LYP/6-31+G(d), CBS-

QB3, and CCSD/6-31+G(d) levels of theory.33–38 CBS-QB3 is part of a series of

“complete basis set” methods which attempt to extrapolate to an infinite basis set as is required to obtain the exact wavefunction. This methodology starts with a B3LYP

69 geometry optimization and vibrational frequency calculation followed by single-point calculations using highly correlated methods combined with extensive basis sets and empirical corrections. The CBS-QB3 method was refined by and evaluated using the

G2/97 test set of compounds which contains experimental data for 148 enthalpies of formation, 88 ionization potentials, 58 electron affinities, and 8 proton affinities.39,40 This method, while slightly more computationally expensive than B3LYP/6-31+G(d) due to the correlated SP calculations, is much more efficient than performing optimizations at the CCSD level of theory and is known to give extremely accurate energetics with an absolute mean error of 1.10 kcal/mol over the entire G2/97 test set38 The BHandHLYP functional was also used to evaluate the radical cation surface of EMC due to its efficacy at the prediction of the thermal carbene insertion product ratios. The basis set used in this case was not DZP as was used by Sulzbach et al.,18 but the 6-31+G(d) basis set which is similar to DZP.

In traditional transition state theory, the apparent rate constant can be derived with the following thermodynamic formula which is a function of temperature as shown in eqn

3.2:

∆ �(�) = Γ(�) � (3.2)

In equation 3.2 G(T) is the temperature-dependent Wigner correction (vide infra).41

Single-point energy calculations were carried out on select intermediates, transition states, and products at the CCSD(T)/6-311++G(d,p)//B3LYP/6-31+G(d) level of theory and with corrections for quantum mechanical tunneling (QMT) where such corrections are taken into account by Wigner’s methodology (eqn. 3.3).42 70

Γ(�) = 1 + (3.3)

All computed stationary points were characterized by vibrational frequency analyses and appropriately confirmed to be minima (zero imaginary vibrational frequencies) or transition states (one imaginary vibrational frequency). Transition states were verified to connect the reactants and products by intrinsic reaction coordinate (IRC) calculations.43

Ethylphenylcarbene, its migration products, and the transition states leading to them were calculated with the B3LYP/6-31+G(d) and CBS-QB3 levels of theory. Single- point energy calculations were carried out at the CCSD(T)/6-311++G(d,p)//B3LYP/6-

31+G(d) for QMT corrections. B3LYP/6-31+G(d), CBS-QB3, and CCSD(T)/6-

311++G(d,p)//B3LYP/6-31+G(d) calculations were carried out on chloromethyl- chlorocarbene and benzyl-chlorocarbene.

Broken symmetry calculations44 where performed on several starting geometries of a dinitrogen carbene complex at the UB3LYP/6-31+G(d) level of theory, but all attempts at locating an open-shell solution to describe a charge-separated carbene radical cation/dinitrogen radical anion state resulted in convergence to a closed-shell solution.

Other ion pairs were investigated to attempt to find a charge-separated complex by swapping nitrogen for electronegative species more likely to hold onto the initially formed “Rydberg” electron, but these calculations also produced only closed-shell solutions. Due to the difficulty of directly describing a charge-separated radical cation/radical anion complex, the carbene systems in question were taken and evaluated

71 as purely radical-cation species in order to approximate the hypothesized rearrangement’s potential energy surface and specifically to evaluate the proposed product distribution.

3.3 Migration Pathways for Ethylmethylcarbene and its Radical Cationic Form

Relative energies of previously optimized transition states, as published by

Sulzbach et al.18 for the migration pathways of ethylmethylcarbene (EMC) at the

BHandHLYP/DZP level of theory, are compared to other levels of theory in Table 3.2 to assess the theoretically predicted thermal distribution of carbene rearrangement products.

The energies provided are the zero–point vibrational energy corrected enthalpies, hence

∆H(0K) and as free energies (298K) (shown in parentheses).

Table 3.2 Computed activation barriers (kcal/mol) for the transition states located from the closed–shell EMC to observed thermal products.a

Product BHandHLYP/DZP18 B3LYP/6-31+G(d) CBS-QB3 CCSD/6-31+G(d) 10.56 (10.67) 9.54 (9.65) 7.01 (7.12) 10.91 (11.04)

6.64 (6.91) 5.24 (5.51) 3.30 (3.57) 7.09 (7.34)

7.43 (7.26) 7.24 (7.15) 5.33 (5.24) 9.13 (8.78)

10.98 (11.71) 11.18 (11.88) 6.68 (7.37) 12.58 (13.31)

20.70 (21.23) 17.00 (17.51) 14.50 (15.01) 19.81 (20.36)

a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for ethylmethylcarbene at the comparable level of theory.

In order to better compare the theoretical results to the experimental pyrolysis performed by Mansoor et al., product yield percentages calculated from transition state

‡ ∆G 298 energies are presented in Table 3.3.

Table 3.3 Percent yields for the thermal decomposition of 3-ethyl-3-methyldiazirine from theoretical calculations and experiment.a

Product BHandHLYP/DZP B3LYP/6-31+G(d) CBS-QB3 CCSD/6-31+G(d) Exp. 0.1 0.1 0.2 0.1 3.3

64 94 94 92 66.6

36 5.9 5.5 8 29.5

0.02 0 0.1 0 0.5

0 0 0 0 0

a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

From Table 3.3, one can observe that BHandHLYP/DZP does the best job at reproducing the experimental pyrolysis data of 3-ethyl-3-methyldiazirine (EMD), while the other methods predict a slightly exaggerated favor for the trans-2-butene product.

However, in reality, small energy differences make a very large effect on computed product distributions so in general, each of the methods does a reasonable job of predicting the thermal distribution. Due to the inclusion of exact exchange and its potential to more effectively describe ethylmethylcarbene (EMC) on the neutral carbene surface, the BH&HLYP functional was explored in order to calculate species on the radical cation surface in Table 3.4. Similar to the above data, calculated percentages based on the radical cation surface date are provided in Table 3.5 alongside Mansoor’s experimental photolysis data.9

Table 3.4 Computed activation barriers (kcal/mol) for the transition states located from ethylmethylcarbene’s radical cation relative to the observed thermal products.a

Product BHandHLYP/6-31+G(d) B3LYP/6-31+G(d) CBS-QB3 CCSD/6-31+G(d) 14.64 (15.00) 14.08 (14.42) 10.10 (10.35) 13.54 (13.14)

3.49 (3.97) 3.27 (3.77) –0.07 (0.36)b 3.04 (2.69)

3.53 (3.82) 3.24 (3.56) –0.25 (0.01)b 2.98 (2.53)

10.48 (11.31) 9.89 (10.76) 3.98 (4.76) 6.9 (8.51)

6.03 (6.61) 5.39 (6.00) 1.66 (2.16) 3.35 (4.62)

a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for ethylmethylcarbene’s radical cation at the comparable level of theory. b While the free energies have positive values, the zero–point corrected CBS–QB3 are predicted to be lower in energy than the starting material. This is due to the high level single-point energy calculations (i.e. coupled cluster methodology) applied as a correction to what is the geometry at the B3LYP/6–31G† level of theory. The computed hypersurfaces do not exactly align in this case.

Product BHandHLYP/6-31+G(d) B3LYP/6-31+G(d) CBS-QB3 CCSD/6-31+G(d) Exp. 0 0 0 0 23.2

44 41 35 43 38

56 58 64 56 34.7

0 0 0.02 0 3.7

0.5 1 1.7 2 0.3

a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

The computational results of the CBS–QB3 calculations on the closed-shell singlet carbene and radical cation surfaces generally follow the trend between the experimental pyrolysis and photolysis yields, the major outlier being 1-butene. trans-2-

Butene is predicted to be lower in yield and cis-2-butene is predicted to increase.

Methylcyclopropane is experimentally shown to increase in yield upon photolysis but is predicted in lower yields on the radical cation surface. While the amount of 1-butene is known to increase in yield by photolysis, the calculated free energy barrier on the carbene radical cation surface was significantly higher than those leading to other products. The average barrier height amongst the different levels of theory tested was ~4.5 kcal/mol and inclusion of corrections for quantum mechanical tunneling did not lower the apparent barrier by a sufficient amount to make any appreciable difference. Finally, and perhaps most interestingly, for the first-time, consideration of the carbene radical cation pathway predicts the formation of isobutene. This is the result of a 1,2-methyl shift on the radical cation surface of the EMC framework. In all cases, the calculated trans-cis ratio is slightly opposite from what is observed experimentally (38:34.7, in favor of trans), but all of the theoretical methods for the carbene radical cation mechanism predict that the transition states for the cis and trans products are similar in energy.

These calculations seemingly fit the data and provide the final missing piece of a

50-year old puzzle. It has already been stated and shown previously that the chemistry of these diazirine compounds is quite rich in the number of species involved and the pathways of decay that are all in competition with one another. While the transition state to 1-butene was predicted to be highly unfavorable on the carbene radical cation surface,

76 computations on this surface are likely to be an approximation of the nature of the true intermediate (a separated radical cation/radical anion pair). It has also been demonstrated

24 by Luk that a surface crossing between the S1 open-shell excited state leading to 1- butene does exist and is potentially energetically accessible upon photolysis of the diazirine precursor. The product distributions from experimental photolysis almost certainly come from a combination of the vibrationally cooled or thermally hot closed- shell carbene ground state; a relaxed, possibly vibrationally cool, open-shell excited S1 state; a carbene radical cation-like intermediate formed as an ion pair in the excited state; and potentially complete rearrangement on the photochemically excited state.

A comparison of the geometries of the closed-shell singlet carbene (B3LYP/6-

31+G(d)), open-shell singlet (CASSCF(8e,8o)/cc–pVTZ),24 and the carbene radical cation species (B3LYP/6–31+G(d)) is quite illuminating (Figure 3.9).

Figure 3.9 Optimized geometries of the closed-shell singlet and the radical cation at the B3LYP/6-31+G(d) level of theory. The open-shell S1 singlet optimized at the CASCCF(8e,8o)/cc-pVTZ level of theory24 is presented in the bottom row.

A visual representation of the geometry of the relaxed S1 excited state is not available, but the corresponding angle for C1–C5–C6 is 140°, almost exactly the same as in the case of the carbene radical cation.24 The molecular geometry of the radical cation is well positioned to become the open-shell singlet if back electron transfer were to occur from the radical ion separated pair.

The geometries of the transition states leading to the final products are consistent and only slightly perturbed by the removal of an electron for EMC (Figures 3.10 and

3.11).

A numerical comparison of geometric features for the transition states in Figure

3.11 are available in Tables 3.6, 3.7, and 3.8.

Table 3.6 Select bond angles and distances for the transition state leading to 1–butene predicted at the B3LYP/6–31+G(d) level of theory.

Carbene Radical Cation Ð C1–C5 –C6 (°) 115 142 Ð C5–C1–H4 (°) 59 52 Ð C1–C5–C6–H8 (°) –101 –96 Bond Length C5–H4 (Å) 1.326 1.242 Bond Length C1–H4 (Å) 1.286 1.443

Table 3.6 shows that the bond angles centered around the carbenic carbon (Ð C1–

C5 –C6) deviate by a significant amount from one another, but almost exactly mirror the starting carbene and radical cation geometries shown in Figure 3.11. The bond angles for

1,2-H migration deviate as well, although the more telling sign of the location of the transition state is in the C5–H4 and C1–H4 bond distances for which it is clearly revealed that the transition state looks much more like the starting material in the case of the radical cation than in the case of the transition state on the neutral carbene surface. The free energy barriers for the carbene and carbene radical cation are 9.65 and 14.42 kcal/mol, respectively, at the B3LYP/6–31+G(d) level of theory (Tables 3.2 and 3.4), and it appears that on the neutral carbene surface, the transition state is later than the transition state on the radical cation surface. The final deviation seen between the neutral and radical cation surfaces is the dihedral angle formed by atoms C1–C5–C6–H8. In the case of the carbene radical cation, a rotation about the C5–C6 bond leads to better overlap of the s(C–H) with the more electron poor carbenic center.

Table 3.7 Select bond angles and distances for the transition state leading to trans-2-butene predicted at the B3LYP/6–31+G(d) level of theory.

Carbene Radical Cation Ð C1–C5 –C6 (°) 115 142 Ð C5–C6–H8 (°) 59 58 Bond Length C5–C6 (Å) 1.398 1.370 Bond Length C6–H8 (Å) 1.280 1.336 Bond Length C5–H8 (Å) 1.328 1.306

Table 3.8 Select bond angles and distances for the transition state leading to cis-2-butene predicted at the B3LYP/6–31+G(d) level of theory.

Carbene Radical Cation Ð C1–C5 –C6 (°) 117 142 Ð C5–C6–H7 (°) 61 59 Bond Length C5–C6 (Å) 1.406 1.369 Bond Length C6–H7 (Å) 1.264 1.318 Bond Length C5–H7 (Å) 1.366 1.325

In Tables 3.7 and 3.8, the calculations show that the transition-state geometries maintain the angle about the carbene center when compared to their respective starting geometries. It is noted that the C5–C6 bond length of the radical cation is contracted slightly in comparison to the carbene. In the case of the transition states leading to the cis and trans products, the migratory hydrogen (H8) is in transit from C6 to C5. Comparison of the C–H bond distances between the transition states leading to the trans and cis products on the neutral carbene surface reveals that H8 is farther from its destination by

0.038 Å in the case of the cis transition state. On the radical cation surface, a similar comparison shows this difference to be half of the carbene surface value at a 0.019 Å difference between trans and cis. The radical cation surface shows less stereochemical preference than in the case of the neutral carbene, something that will also be apparent in the case of ethylphenylcarbene (EPC, vide infra).

The formation of the transition state leading to the insertion of the carbene center

C3 into the C1–H8 bond forming methylcyclopropane and the methyl migration geometric parameters are well conserved between the neutral carbene and radical cation surfaces. It is important to note that as with all of the other species on the radical cation surface, the

C2–C3–C9 bond angle for methylcyclopropane and C2–C1–C5 bond angle for isobutene

(both originally carbenic centers) maintain the ~140° angle of the starting intermediate.

In the case of isobutene, on the carbene surface, this C2–C1–C5 bond angle is 113°, close to that of what is expected for an sp2-hybridized carbon. While there seems to be little geometric insight into why the methyl migration pathway becomes viable on the radical cation surface, it is likely due to the fact that, for an electron deficient species, hydrogen

82 migration pathways have an increased penalty when compared to the migration of methyl group as is reflected in the relative energetics (Table 3.4). Also, when comparing Table

3.2 to Table 3.4, while the relative transition-state barriers are lower for each migration except for the case of 1-butene, the relative barriers decrease by about 3 kcal/mol going from the carbene to the radical cation surface. However, in the case of isobutene, this barrier is lowered by around 12 kcal/mol!

A natural population analysis performed on the EMC radical cation species at the

B3LYP/6-31+G(d) as implemented by natural bond order (NBO version 3.1)45 in the

Gaussian ‘16 suite of programs provides evidence in agreement with the observed lowering in relative energy barrier leading to isobutene when compared to the neutral carbene surface. If one thinks of the carbon-centered radical cation and the extent to which it is carbocation-like, the addition of an alkyl group is likely to have an increased stabilizing effect when compared to a carbon-centered radical. The difference in degrees of stabilization is rationalized by the mixing of filled π(CH3) (or other alkyl substituent) orbitals with an empty p-type orbital for carbocations, while in the case of radicals, it is a filled π(CH3) orbital interacting with another partially filled orbital. This three electron two orbital mixing has less overall stabilization than in the two electron two orbital case.46 At the B3LYP/6-31+G(d) level of theory the carbenic radical cation center of the carbene geometry carries the majority of the positive charge at +0.88. Because of this charge localization, the migratory effect of an alkyl group would be expected to be fairly large, just as for carbocations.

3.4 Product Distributions of Ethylphenylcarbene and its Radical Cationic Form

Preliminary data on the photolysis of (1-diazopropyl)benzene (Figure 3.12) shows a wavelength dependent decomposition of the starting material to produce the cis and trans products (Figure 3.13).

500 nm

250 nm +

X Y

N N N2

Figure 3.12 Predicted reaction pathways for the photolysis of (1-diazopropyl)benzene to cis and trans products.

Figure 3.13 Ratio of cis to trans product as a function of wavelength for the photolysis of (1-diazopropyl)benzene.

No product was observed at wavelengths of 350, 400, and 450 nm which is consistent with the predicted absorption spectra (Table 3.9) and the lack of diazo absorption at these wavelengths.

Table 3.9 Vertical excitation energies (TD-B3LYP/6-31+G(d), nm) of the (1– diazopropyl)benzene precursor.

Wavelength Oscillator State (nm) Strength S1 531 0.0001

S2 288 0.0386

S3 276 0.3995

S4 265 0.0000

S5 262 0.0028

S6 243 0.0001

S7 242 0.0012

S8 233 0.0001

S9 223 0.0752

S10 219 0.0289

According to the TD-DFT calculations, the S1 state of the precursor is pumped at an experimental excitation wavelength of 500 nm. The S2 and S3 states are both likely to be accessible with 300 nm light considering the oscillator strengths indicate a lmax at 276 nm, but also show a relatively strong transition at 288 nm. The use of 265 nm light is predicted to align with a dark state with zero oscillator strength, and higher-lying excited states, such as S5–S7, are pumped with 250 nm light.

The alkene migration products were found to interconvert upon extended duration of photolysis as is expected.47 Data points collected before apparent isomerization yield the results in Figure 3.13. Vacuum pyrolysis of the (1-diazopropyl)benzene precursor was performed in a previous study by Fox et al. in 1992.48 Their results showed an average of

1:4 cis to trans ratio, similar to what is observed at relatively long wavelengths of light

(Figure 3.13). Upon photolysis with short wavelength UV light (250 nm), an apparent inversion of product ratios is observed, now favoring a cis to trans ratio of ~ 2:1.

Again, with a nitrogenous precursor, we see an apparent inversion between pyrolysis and photolysis data. A similar set of computations to those performed on EMC were carried out on the neutral carbene and radical cation surfaces of the carbene derived from (1-diazopropyl)benzene, i.e., ethylphenylcarbene (EPC), to further support the hypothesis of a mechanistically relevant carbene radical ion pair intermediate. In this case, with a lower number of products, single point energy calculations were performed at the CCSD(T)/6-311++G(d,p)//B3LYP/6-31+G(d) level of theory and were utilized to produce Wigner corrected apparent free energy barriers. The energetic results of these calculations are compiled in Tables 3.10 and 3.12 with the derived product percentages in

Tables 3.11 and 3.13.

Table 3.10 Computed activation barriers (kcal/mol) for the transition states located on the closed-shell ethylphenylcarbene (EPC) surface.a

CCSD(T)/6-311++G(d,p)// Product B3LYP/6-31+G(d) CBS-QB3 B3LYP/6-31+G(d)b cis 8.26 (8.47) 5.00 (5.16) 12.74 trans 6.27 (6.68) 3.37 (3.75) 11.1 a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for ethylphenylcarbene at the comparable level of theory. b Numbers represent corrected apparent free energy barriers to rearrangement derived from Wigner tunneling corrections at 298K at the displayed level of theory.

Table 3.11 Percent distributions based on activation barriers on the closed-shell carbene surface of ethylphenylcarbene (EPC) compared to estimates from experiment.a

CCSD(T)/6-311++G(d,p)// Product B3LYP/6-31+G(d) CBS-QB3 Exp. B3LYP/6-31+G(d) cis 5 8 6 20 trans 95 92 94 80 a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

Table 3.12 Computed relative energies (kcal/mol) for the transition states located on the radical cation surface of the ethylphenylcarbene (EPC) framework.

CCSD(T)/6-311++G(d,p)// Product B3LYP/6-31+G(d) CBS-QB3 B3LYP/6-31+G(d)b cis 14.33 (14.68) 10.60 (11.00) 14 trans 14.38 (14.89) 10.96 (11.49) 14.25 a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for ethylphenylcarbene’s radical cation at the comparable level of theory. b Numbers represent corrected apparent free energy barriers to rearrangement derived from Wigner tunneling corrections at 298K at the displayed level of theory.

Product B3LYP/6-31+G(d) CBS-QB3 CCSD(T)/6-311++G(d,p)// Exp. B3LYP/6-31+G(d) cis 59 70 60 66 trans 41 30 40 34 a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

As was the result with ethylmethylcarbene formation, for the first time, computations on the radical cation surface were able to predict the experimental photolysis yields with remarkable accuracy. The CBS-QB3 results appear to be the most predictive similar to computational predictions for EMC. The quantum mechanical tunneling corrections showed only minimal improvement in predictive capability. As was seen previously, the rearrangement on the radical cation surface shows less stereochemical preference than on the neutral carbene surface. A comparison of the optimized transition state geometries at the B3LYP/6-31+G(d) level of theory are shown in Figure 3.14.

When considering the geometric aspects of the transition states involved in the rearrangement of EMC (Tables 3.6, 3.7, and 3.8), several factors remain consistent on the radical cation surface of EPC (Tables 3.14 and 3.15).

Table 3.14 Select bond angles and distances for the transition state leading to cis- methylstyrene predicted at the B3LYP/6–31+G(d) level of theory.

Radical Carbene Cation ÐC4–C12–C13 (°) 119 144 ÐC5–C4–C12–C13 (°) 122 113 C13–H14 (Å) 1.245 1.277 C12–H14 (Å) 1.390 1.370 C4–C12 (Å) 1.465 1.400 C12–C13 (Å) 1.409 1.375

Table 3.15 Select bond angles and distances for the transition state leading to trans- methylstyrene predicted at the B3LYP/6–31+G(d) level of theory.

Radical Carbene Cation Ð C4–C12–C13 (°) 116 143 Ð C5–C4–C12–C13 (°) 134 117 C13–C14 (Å) 1.268 1.293 C12–C14 (Å) 1.346 1.346 C4–C12 (Å) 1.470 1.402 C12–C13 (Å) 1.401 1.375

The bond angle centered at the carbenic carbon is expanded on the radical cation surface to a value of ~144°. This observation is consistent when compared to all other radical cation geometries for EMC and EPC. Along with the enlarged bond angle, the radical cation also has a contracted bond length (when compared to the neutral carbene) between C12–C13, particularly in the case of the transition state leading to the cis product, similar to EMC. The bond connecting the benzene ring to the carbene center is shortened by a considerable amount, ~0.5 Å, on the radical cation surface compared to its neutral carbene counterpart. Finally, comparison of the dihedral angles C5–C4–C12–C13 for both transition states, cis and trans, reveal that the radical cation leaves a sp2-type SOMO orthogonal to the plane of the ring (Figure 3.15).

In the case of the carbene, it is seen that the geometric preference is altered in order to place the p-type LUMO in conjugation with the benzene ring (Figure 3.16). The

91 value for the C5–C4–C12–C13 is 134° in the case of the carbene and 114° in the case of the carbene radical cation (Table 3.15). For reference, the carbene dihedral angle would need to be 180° to make the p-orbital fully orthogonal with the plane of the ring. The corresponding value for the SOMO to be fully orthogonal to the ring would be 90°. An explanation for the incomplete conjugation arises from steric clashes between the hydrogens substituted on the ortho positions of the rings with the hydrogens on the carbene containing chain. These steric considerations are exacerbated in the case of the transition states leading to the cis isomers, but for the carbene radical cation, this is somewhat alleviated by the expansion of the C4–C12–C13 angle (Table 3.14, Figure 3.11).

Figure 3.16 EPC, neutral carbene transition state to trans product, showing the LUMO with the p-type orbital on the carbene center orthogonal to the plane of the benzene ring. A structure without the overlapping surface is provided for clarity and comparison on the right.

Our original hypothesis which invokes the carbene radical ion separated pair comes as a result of photolysis of a diazirine and not a diazo compound. As was

92 discussed in chapter 2 of this thesis, diazo and diazirine compounds are known to photochemically interconvert and this appears to be the predominant photochemical pathway for ethyl 2-diazo-3,3,3-trifluoropropanoate.49 In this case, with sufficiently energetic light, it is theorized that the diazo compound interconverts to the diazirine in the excited state and the corresponding diazirine decomposes under a separated carbene radical ion regime. Further photolysis experiments on the diazirine compound could provide additional support for this theory.

3.5 Results from Benzylchlorocarbene, Chloromethyl-chlorocarbene, and tert- butylcarbene

Maintaining the theme of the current chapter, calculations were performed on select chlorinated carbene derivatives as well as a theoretical study of tert-butylcarbene

(Figure 3.17). The experimental yields for the photolysis of chloromethyl-chlorodiazirine and benzylchlorodiazirine were taken from the work of Bonneau and Liu et al.10 Data for the pyrolysis and photolyis of tert–butyldiazirine was taken from the work of Shechter et al.11

Cl Cl H Cl

Figure 3.17 Benzylchlorocarbene, chloromethyl-chlorocarbene, and tert-butylcarbene as formed from the corresponding diazirine compounds.

Computational results as compared to the experimental data are tabulated in

Tables 3.16–3.25. Tables 3.16 and 3.17 show that calculations on the neutral carbene surface reproduce the experimental pyrolysis results quite well with CBS–QB3. Due to this agreement, further QMT calculations were not undertaken for benzylchlorocarbene.

When the transition states for the same 1,2-hydrogen migrations were located on the carbene radical cation surface, the results differed by an appreciable amount, showing that if a radical ion mechanism was operative, then the distribution should be much closer to 1:1 at the B3LYP/6–31+G(d) level of theory and an ~4:1 ratio at the CBS-QB3 level of theory. An increase in the yield of cis alkene is apparent upon the decomposition of the diazirine by photolysis and the computational data suggest that under a radical cation-like mechanism, this should be the case. It is apparent that the pyrolysis product distribution comes as a result of a thermalized singlet carbene perhaps as favored by the very significant energetic bias towards the closed-shell singlet due to the chloro substituent on the carbene center.50 Furthermore, it is likely that the increase in cis alkene comes as a result of a purely radical cation-like intermediate. The excited open-shell singlet carbene pathway could effectively be eliminated by the substituent effect of the chlorine on the carbene center. In this sense, while benzylchlorocarbene is similar to the previously investigated ethylphenylcarbene (vide supra), the number of avenues leading to rearranged products is decreased, thereby adding more confidence in the operative mechanism.

Table 3.16 Computed Activation Barriers (kcal/mol) for the transition states located from the closed-shell benzylchlorocarbene to observed thermal products.a

Product B3LYP/6-31+G(d) CBS-QB3 cis 9.57 (9.97) 7.41 (8.01) trans 6.85 (7.56) 9.40 (9.71) a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for benzylchlorocarbene at the comparable level of theory.

Table 3.17 Percent distributions based on activation barriers on the closed-shell carbene surface of benzylchlorocarbene compared to estimates from experimental thermolysis.a

Product B3LYP/6-31+G(d) CBS-QB3 Exp.10 cis 2 5 11 trans 98 95 89 a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

Table 3.18 Theoretical results from calculations on the radical cation surface of benzylchlorocarbene.a

Product B3LYP/6-31+G(d) CBS-QB3 cis 18.79 (18.45) 9.40 (9.71) trans 18.64 (18.36) 7.41 (8.01) a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for benzylchlorocarbene at the comparable level of theory.

Table 3.19 Percent distributions based on activation barriers on the closed-shell carbene surface of benzylchlorocarbene compared to estimates from experimental photolysis.a

Product B3LYP/6-31+G(d) CBS-QB3 Exp. cis 47 24 25 trans 53 76 75 a Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

While investigating chloromethyl-chlorocarbene, results from calculations on the neutral carbene surface appear in agreement to experimental pyrolysis results. The results performed at the CCSD(T)/6-311++G(d,p)//B3LYP/6-31+G(d) including corrections for quantum mechanical tunneling provide the smallest gap in apparent free energy barriers at 3.62 kcal/mol which is within 1 kcal/mol of predicting a visible percentage of trans product. RIES is hypothesized to be more efficient for chloromethyl-chlorodiazirine than for benzylchlorodiazirine based on photoacoustic calorimetry measurements carried out by Liu et al.10 With this experimental result in mind computations were performed on the radical cation surface of the chloromethyl-chlorocarbene framework. The results show a decrease in the difference between the relative barriers to cis and trans product formation.

This decrease in difference leads to the prediction that a non-zero, albeit small amount of trans product would be formed. The general correlation remains conserved as going from pyrolysis to photolysis there is an increase in trans alkene, while computationally, moving from the neutral carbene to radical cation surface also predicts an increase in trans alkene. This favorable result provides more support for the proposed mechanism of action.

Table 3.20 Theoretical results from calculations on the neutral carbene surface of chloromethyl-chlorocarbene.a

CCSD(T)/6-311++G(d,p)// Product B3LYP/6-31+G(d) CBS-QB3 B3LYP/6-31+G(d)b cis 10.15 (10.43) 8.67 (8.97) 9.11 trans 16.25 (16.68) 13.74 (14.19) 12.73 a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for chloromethyl-chlorocarbene at the comparable level of theory. b Numbers represent corrected apparent free energy barriers to rearrangement derived from Wigner tunneling corrections at 298K at the displayed level of theory.

Table 3.21 Predicted percent yields for the thermal decomposition of chloromethyl-chloro carbene from theoretical calculations and experimental pyrolysis data.a,b

B3LYP/6- CCSD(T)/6-311+G(d,p)// Product CBS-QB3 % Exp. 31+G(d) B3LYP/6-31+G(d) cis 100 100 100 94 trans 0 0 0 6 a Pyrolysis performed at 110° C bPercent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

Table 3.22 Theoretical results from calculations on the radical cation surface of chloromethyl-chlorocarbene.a

CCSD(T)/6–311++G(d,p)// Product B3LYP/6–31+G(d) CBS–QB3 B3LYP/6-31+G(d)b cis 10.54 (10.81) 9.30 (9.58) 12.8 12.85 trans 16.14 (14.47) 15.08 (13.30) a Energies as provided as ∆H‡(0K) and as ∆G‡(298K) in parentheses. All energies are relative to that for chloromethyl-chlorocarbene at the comparable level of theory. b Numbers represent corrected apparent free energy barriers to rearrangement derived from Wigner tunneling corrections at 298K at the displayed level of theory.

Table 3.23 Predicted percent yields for the photochemical decomposition of chloromethyl- chloro carbene from theoretical calculations on the radical cation surface as well as experimental photolysis data.a,b

CCSD(T)/6–311++G(d,p)// Product B3LYP/6-31+G(d) CBS-QB3 Exp. B3LYP/6–31+G(d) cis 100 99.8 98 84 trans 0 0.2 2 16 a From photolysis experiments performed at 10° C b Percent yields derived from calculated ∆G‡(298K) values at the corresponding level of theory.

A final computational case study involving the pyrolysis and photolysis of tert- butyldiazirine was undertaken due to the fact that the rearrangement products were not limited to cis and trans alkenes, but to a more complicated C–H insertion product, i.e., formation of 1,1-dimethylcyclopropane, and a product resulting from a 1,2-methyl migration (trimethylethylene). The results of computations on the relevant neutral carbene and radical cation surfaces compared to the experimental values are listed in

Tables 3.20 and 3.21.

The free energy barrier leading to methylcyclopropane is extremely low on the carbene surface at 0.79 kcal/mol, while the barrier for the formation of trimethylethylene is 2.6 kcal/mol, also fairly low. The flat nature of this PES could provide an explanation to difficulties encountered when tracing these pathways on the carbene radical cation surface

Computations on the radical cation surface yielded only trimethylethylene with no locatable transition state. In fact, the geometry of the neutral carbene when optimized as a

98 radical cation is not even a stationary point on the PES, the structure instantaneously follows a steepest decent path to trimethylethylene which is a local minimum.

It is possible that there is a mixture of radical ion pair chemistry as well as thermalized carbene chemistry upon photolysis. In a dynamic sense, in the excited state, it could be that the diazirine is able to follow an essentially “barrierless” pathway that bifurcates and funnels to the products. The alkene product is predicted to be lower in energy than its 1,1-dimethylcyclopropane counterpart by 18.45 kcal/mol (B3LYP/6-

31+G(d)) on the radical cation surface. A transition state was located on this surface and while the traditional carbene geometry was not a stationary point, the transition state located was found to connect trimethylethylene to 1,1-dimethylcyclopropane. This free energy barrier was calculated to be 62 kcal/mol going from the alkene to the cyclic product. This barrier is certainly insurmountable on the ground state surface, but with vibrationally hot molecules, it might be possible for them to interconvert. It should be noted that any carbene that has a hydrogen substituent on the carbenic center spontaneously optimizes to the geometry of the alkene on the radical cation surface

(results of these calculations not included in this work).

Table 3.24 Comparison of product distributions from theoretical calculations and experimental pyrolysis of tert-butyldiazirine (calculations on the neutral carbene surface).

Exp. ∆ Product B3LYP/6–31+G(d) % %11 96 90

4 10

Table 3.25 Comparison of product distributions from theoretical calculations and experimental photolysis of tert-butyldiazirine (calculations on the carbene radical cation surface).

Product B3LYP/6–31+G* % Exp. hn %11 0 50

100 50

Calculations were also performed on other carbene species previously investigated by Sulzbach et al.18 (Figure 3.18), but due to extremely similar results between photolysis and pyrolysis, there was no way to confidently ascribe a particular rearrangement product as resulting from a particular intermediate species (closed-shell carbene, excited open-shell carbene, or radical-cation).

100

cyclobutylidene 2-norbornylidene 2-bicyclo[2.1.1]-hexylidene

Figure 3.18 Computationally studied structures with no distinguishing features between photolysis and pyrolysis.

These species were studied extensively through experiments by Shechter,

Friedman et al., Platz et al., and Kirmse et al.51,52

3.6 Conclusions

Through the application of computational chemistry at several different levels of theory on several different systems along with available experimental data, it was possible to derive approximate photolysis product distributions with surprising accuracy.

These results suggest an additional pathway is available for the decomposition of nitrogenous precursors when exposed to short wavelength irradiation. The true nature of what has been defined as rearrangement in the excited state may actually be rearrangement on a carbene radical cation/radical anion Rydberg-like surface. This does not rule out the other possibility that a concomitant rearrangement of the carbene precursor, coupled with N2 expulsion on the upper excited state surface, of the diazirine.

The ability to compute such a RIES process reliably is a potentially fruitless endeavor given current available methodology.

101

However, it is important to reiterate that that the separated radical ion pair pathway is an additional mechanistic option to an already complex reaction landscape for carbenes as reactive intermediates. The identified possibilities are rearrangement from a thermalized singlet carbene, a thermalized open-shell singlet carbene which decays to products from the S1 state, a concerted rearrangement in the upper excited state of the diazirine, and finally by rearrangement on a carbene radical cation-like surface.

Vibrationally hot versions for each of these pathways are also viable.

An interesting extension to this work would be to track the molecular dynamics of the excited states of EMD over time using ab initio multireference methods like

CASSCF. Such methodology is computationally very expensive and functionally difficult, but can be performed utilizing the DYNAMIX program as implemented in

MOLCAS 8.53,54 From a dynamics simulation while observing the excited diazirine evolve along a time course leading to a surface hopping and expulsion of nitrogen one could perform a population analysis at every time step to see exactly how the electrons are distributed throughout the entire process of carbene formation from the diazirine excited state.

3.7 References for Chapter 3

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Chapter 4. Direct Observation of an Alkylidenecarbene by Ultrafast Transient Absorption Spectroscopy

4.1 Introduction

The work in this chapter was performed in collaboration with Lili Du, Xin Lan,

David Lee Phillips (University of Hong Kong) as well as Xi Yang, and Dasan

Thamattoor (Colby College). Lili Du and Xin Lan performed the ultrafast time-resolved laser experiments and the synthesis was performed by Xi Yang. All computational work presented below is the work of the author.

It was recently reported that the phenanthrene-based methylenecyclopropane, 1-

(1-phenylethylidene)-1a,9b-dihydro-1H-cyclopropa[l]-phenanthrene (1), produced singlet a-methylbenzylidenecarbene (2) upon photolysis in solution (Figure 4.1).1 The carbene then undergoes a Fritsch-Buttenberg-Wiechell (FBW)-type rearrangement2 to produce the corresponding alkyne 3.

108

Figure 4.1 Photochemical conversion of 1-(1-phenylethylidene)-1a,9b-dihydro-1H- cyclopropa[l]-phenanthrene (1) to phenylpropyne (3) through a predicted vinyl carbene intermediate (2).

Furthermore, using 13C-labeled precursors that produced 2 with the label at the benzylic carbon, Thamatoor and co-workers recently demonstrated that the rearrangement of 2-13C occurs exclusively by a 1,2-phenyl shift rather than a methyl shift.1 These experimental observations were found to be consistent with the results of theoretical calculations.1

Remarkably, although time-resolved laser flash photolysis (LFP) has played a critical role in studying various types of carbenes,3 there appear to be no reports attesting to the use of this method for the investigation of alkylidenecarbenes. Perhaps this conspicuous void in the literature may be attributed to the lack of photochemical precursors suitable for such studies. Herein we report a photochemical study of precursor

1 using femtosecond transient absorption (fs-TA) spectroscopy to directly detect and characterize the alkylidenecarbene 2. To the best of our knowledge, this work is the first direct spectroscopic observation of an alkylidenecarbene in solution.

109

4.2 Computational Methods

All calculations were performed using the Gaussian ’16 suite of programs.4

Geometry optimizations and vibrational frequency calculations for species 1, 12, 12-npl, and 3 were performed at the B3LYP/6–311+G(d,p)5–9 level of theory with and without implicit solvation in acetonitrile with the SMD model.10 TD-B3LYP/6–311+G(d,p)11 calculations were carried out on each of these species and in the case of 1, the first excited state was optimized with and without implicit solvation. Optimization and frequency calculations on species 12 at the CASSCF(10e,10o)/6–311+G(d,p)12 in the gas phase were also performed. All computed stationary points were characterized by vibrational frequency analyses and appropriately confirmed to be minima (zero imaginary vibrational frequencies).

4.3 Results

Photolysis of 1 was investigated by fs-TA in MeCN solution by irradiation at 267 nm (Figure 4.2).13 The initial spectrum at 1 ps shows broad bands at 372 nm and 421 nm.

Both of these bands decay rapidly from 1.2 to 12 ps, while the 325 nm tail feature from a higher energy band increases in relative intensity to these two bands. However, due to the limitation of our instrumentation, we were not able to observe the spectra below 325 nm.

The relative intensity of the 325 nm tail reaches a maximum at 12 ps, as both bands at 372 and 421 nm subside to the baseline. Subsequently, the tail at 325 nm decays over the next

60 ps.

110

1.2 ps 1.5 ps 2.1 ps 2.9 ps

4.0 ps -2 5.4 ps 1 7.6 ps 12 ps

OD /10 OD 19 ps D 79 ps

0 350 400 450 500 550 600 650 Wavelength (nm)

Figure 4.2 The fs-TA UV-vis spectra of precursor 1 obtained after 267 nm excitation in MeCN are shown.

Calculations were performed, using the Gaussian ’16 suite of programs,4 for comparison of theoretical predictions with the experimental results. At the TD-B3LYP/6-

311+G(d,p) level of theory,5–10 the ground state of phenanthrene precursor 1 is calculated to have a strong absorption around 280 nm in CH3CN and the longest wavelength absorption occurs at about 300 nm (Table 4.1).

111

Table 4.1 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) of precursor 1

Energy / Oscillator State eV (nm) Strength S1 4.0 (306) 0.5856

S2 4.2 (298) 0.0020

S3 4.2 (293) 0.0753

S4 4.4 (284) 0.8557

S5 4.6 (271) 0.1520

S6 4.6 (270) 0.0545

S7 4.8 (259) 0.0025

S8 4.9 (254) 0.0180

S9 4.9 (252) 0.0924

S10 4.9 (251) 0.0239

The optimized (relaxed) S1 excited state of the photoprecursor (1) is calculated in the gas phase to have a lmax of 357 nm and a much weaker (< 20x) absorption at 437 nm

(by comparison of the computed oscillator strengths, Table 4.2). The solvated (CH3CN), relaxed S1 state has strong absorptions predicted at 340 and 370 nm and a slightly weaker absorption at 449 nm (Table 4.3). These absorbances are consistent with the longer wavelength peaks that are observed in the transient absorption spectrum that decay over time. A comparison of the optimized ground state and the optimized S1 excited state geometries of 1 are presented in Figure 4.3. In the S1 state, the geometry of alkylidene moiety is distorted considerably from the ground state, essentially placing it above the phenanthrene ring system.

112

Figure 4.3 Optimized ground state structure of 1 and its optimized, relaxed S1 excited state respectively at the (TD-B3LYP/6-311+G(d,p), SMD, CH3CN) level of theory.

Table 4.2 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)) for the relaxed S1 state of 1

Energy / Oscillator State eV (nm) Strength S1 2.8 (437) 0.0085

S2 3.5 (357) 0.1798

S3 3.8 (328) 0.1132

S4 4.0 (310) 0.1652

S5 4.1 (303) 0.0713

S6 4.2 (298) 0.0876

S7 4.3 (287) 0.0313

S8 4.4 (281) 0.0052

S9 4.7 (266) 0.0084

S10 4.7 (262) 0.0164

113

Table 4.3 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for the relaxed S1 state of 1

Energy / Oscillator State eV (nm) Strength S1 2.8 (449) 0.0563

S2 3.3 (375) 0.4457

S3 3.6 (340) 0.5165

S4 3.9 (319) 0.1351

S5 4.1 (306) 0.0983

S6 4.1 (204) 0.1808

S7 4.3 (290) 0.0417

S8 4.4 (283) 0.0030

S9 4.6 (269) 0.0501

S10 4.7 (266) 0.0870

Previous DFT calculations (B3LYP/6-311+G(d,p)) indicated that singlet carbene

(12) has two nearly degenerate conformations, one with the methyl group coplanar to the phenyl ring (12-pl) and the other, a nonplanar version, with the methyl group twisted out of plane (12-npl).1 To evaluate if 12 possessed a multireference wavefunction,

CASSCF(10,10)/6–311+G(d,p) calculations11 were employed using the planar carbene

(12-pl) geometry as a model. The active space included ten electrons and ten orbitals, three π and three π* orbitals from the benzene ring, one π and one π* orbital from the vinyl group, and one sp hybrid type orbital and one unhybridized p-type orbital on the terminus of the vinyl group (Figure 4.4).

114

Figure 4.4 Optimized active orbitals for species 12-pl at the CASSCF(10,10)/6- 311+G(d,p) level of theory.

The final one-electron density matrix (Table 4.4) reveals that 9.6 electrons are localized to the 5 occupied orbitals and only 0.4 electrons are localized in the LUMO+1 and LUMO+2 orbitals.

Table 4.4 Final one electron symbolic density matrix for 12-pl.

115

The geometry for the planar carbene species was optimized and verified to be a local minimum by vibrational frequency analysis. These CASSCF results are consistent with the previous DFT results. As the CASSCF reference wavefunction is dominated by a closed-shell description, geometry optimizations, frequency analyses, and vertical excitations for the two conformers of 12 were performed at the B3LYP/6–311+G(d,p) level of theory in both the gas phase and with an implicit solvation model (SMD, acetonitrile).12 These calculations reveal that the twisted geometry is lower in energy than the planar form by 0.5 kcal/mol (∆G) with implicit solvation. Additionally, the dihedral angle of the twisted geometry goes from 69° in the gas phase to 85° in acetonitrile, as shown in Figure 2. It is noteworthy that the twisted geometry looks particularly well oriented for phenyl migration. The angles containing carbons two, three, and the divalent carbon are 109° in the gas phase and 86° in acetonitrile (Figure 4.5).

Figure 4.5 Optimized geometries of carbene 12-npl in the gas phase (left) and acetonitrile (right).

116

Calculations were performed at the TD-B3LYP/6-311+G(d,p) level of theory on both conformers of the carbene in the gas phase as well as with implicit solvation

(CH3CN). In either phase, the maximum absorbance wavelengths for both of these conformers are predicted to be below 300 nm (Tables 4.5-4.8). In solution, the twisted

1 carbene ( 2-npl) has a computed lmax at 206 nm, and two separate, though only slightly weaker, absorbances at 249 and 288 nm as well as a very weak absorbance at 328 nm

1 (Table 4.8). In acetonitrile, the planar carbene ( 2-pl) has a predicted lmax located at 222 and 265 nm (Table 4.5). The calculated UV-vis spectra of both forms of 12 (planar and non-planar) are displayed in Figure 4.6.

117

Table 4.5 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)) for species 12-pl.

Energy / Oscillator State eV (nm) Strength S1 2.8 (444) 0.0004

S2 4.1 (305) 0.0029

S3 4.2 (293) 0.0001

S4 4.9 (254) 0.0269

S5 4.9 (251) 0.0004

S6 5.0 (252) 0.2921

S7 5.6 (220) 0.0112

S8 5.8 (214) 0.0003

S9 5.9 (210) 0.1965

S10 6.3 (197) 0.0058

1 Table 4.6 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species 2- pl. Energy / Oscillator State eV (nm) Strength S1 2.9 (430) 0.0010

S2 4.2 (295) 0.0002

S3 4.3 (289) 0.0157

S4 4.7 (265) 0.6616

S5 4.9 (253) 0.0077

S6 4.9 (252) 0.0012

S7 5.6 (222) 0.5653

S8 5.8 (214) 0.0286

S9 6.1 (205) 0.0019

S10 6.1 (203) 0.3807

118

Table 4.7 Vertical excitation energies (TD-B3LYP/6-311+G(d,p)), for species 12-npl. Energy / Oscillator State eV (nm) Strength S1 3.1 (406) 0.0071

S2 3.8 (329) 0.0012

S3 4.1 (298) 0.0146

S4 4.4 (283) 0.0946

S5 5.4 (231) 0.0113

S6 5.6 (221) 0.0482

S7 5.9 (212) 0.0104

S8 6.1 (205) 0.0064

S9 6.2 (201) 0.0148

S10 6.2 (199) 0.0045

1 Table 4.8 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species 2- npl.

Energy / Oscillator State eV (nm) Strength S1 3.8 (328) 0.0001

S2 4.3 (288) 0.3361

S3 4.5 (275) 0.0945

S4 5.0 (249) 0.3481

S5 5.6 (223) 0.0596

S6 5.7 (218) 0.1432

S7 6.0 (206) 0.5376

S8 6.2 (199) 0.1516

S9 6.4 (195) 0.0197

S10 6.5 (191) 0.0089

119

Figure 4.6 Computed UV-vis spectrum (TD-B3LYP/6-311+G(d,p), CH3CN) of planar (black) and nonplanar (red) carbene 12.

Although the positioning of the maximal absorbance wavelength cannot be observed in the experimental spectrum, the tail observed at 325 nm is tentatively assigned to the carbene intermediate. Even though the energies of the planar and nonplanar forms of 12 are nearly degenerate, the calculated UV-vis spectrum of the non-planar form of the carbene (12-npl) is in better agreement with the experimental results at 12 ps in Figure

4.7. Therefore, the decreasing intensity of the bands at 372 and 421 nm, which could be attributed to the singlet excited state of the precursor 1,14 spontaneously give rise to a new longer-lived intermediate, namely the singlet carbene 12.

120

12b Epsilon

300 350 400 450 500 550 600 650

OD 12 ps D

300 350 400 450 500 550 600 650 Wavelength (nm)

Figure 4.7 Computed (top) UV-vis spectrum (TD-B3LYP/6-311+G(d,p), CH3CN) and the observed (bottom) fs-TA spectrum at 12 ps in MeCN solution of non-planar carbene 12.

The temporal dependence of the transient absorption intensity of the initial species at 372 and 325 nm are displayed in Figures 4.8 and 4.9, respectively. The kinetics at 372 nm could be fit by a single exponential function as shown in Figure 4.6 and the time constant for decay of the singlet excited state of 1 as well as the generation of the 12 is around 4.0 ps.

121

Kinetics at 372 nm -2 t = 4.0 ps

1 1

OD /10 OD D

0 0 20 40 60 80 Time delay (ps)

Figure 4.8 Kinetics at 372 nm of precursor 1 after excitation by 267 nm are shown. The solid red line indicates a fitting of the data using a single exponential function.

Furthermore, as can be seen from Figure 6, 12 decays over a period of 13.3 ps which can be taken as the upper limit for the rate of the 1,2-phenyl shift, the primary pathway converting 12 into 1- phenylpropyne 3. The alkyne product does have a calculated lmax at 262 nm (Table 4.8), but as the experimental 325 tail grows in and then decays to baseline, it is unlikely to be related to the alkyne product. It is likely the decay of the 325 nm peak would correspond to a peak that rises around 260 nm with a similar time constant of 13.3 ps, but this portion of the UV-vis spectrum was not observable.

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Table 4.9 Vertical excitation energies (TD-B3LYP/6-311+G(d,p), CH3CN) for species 3.

Energy / Oscillator State eV (nm) Strength S1 4.7 (262) 0.7968 S2 4.9 (254) 0.0026 S3 5.2 (240) 0.0002 S4 5.6 (221) 0.5213 S5 5.7 (216) 0.0058 S6 6.0 (205) 0.0012 S7 6.1 (203) 0.5638 S8 6.2 (199) 0.0031 S9 6.3 (198) 0.0003 S10 6.5 (190) 0.0000

Kinetics at 325 nm t = 4.5 ps 1 1 t = 13.3 ps 2 -2 OD /10 OD D

0 0 10 20 30 40 50 60 70 80 Time delay (ps)

Figure 4.9 Kinetics at 325 nm of precursor 1 after excitation by 267 nm are shown. The solid red line indicates a fitting of the data using a single exponential function.

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4.5 Conclusion

In summary, we have used fs-TA UV-vis spectroscopy to observe the generation of alkylidenecarbene 12 from the corresponding phenanthrene-based precursor (1) in 4.0 ps. The conversion of 12 into the alkyne 3 via the known 1,2-phenyl shift was found to occur over 13.3 ps. The calculated UV-vis information for the respective species was critical in rationalizing the experimental results for the first detection of an alkylidenecarbene as a reactive intermediate.

4.6 References for Chapter 4

(1) Yang, X.; Languet, K.; Thamattoor, D. M. J. Org. Chem. 2016, 81, 8194.

(2) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319. (b) Buttenberg, W. P. Liebigs

Ann. Chem. 1894, 279, 324. (c) Wiechell, H. Liebigs Ann. Chem.1894, 279, 337.

(3) (a) Moss, R. A.; Wang, L.; Hoijemberg, P. A.; Krogh-Jespersen, K. Photochem.

Photobiol. 2014, 90, 287. (b) Moss, R. A. J. Phys. Org. Chem. 2011, 24, 866. (c)

Moss, R. A. J. Phys. Org. Chem. 2009, 22, 265. (d) Moss, R. A.; Tian, J.; Chu, G.;

Sauers, R. R.; Krogh-Jespersen, K. Pure Appl. Chem. 2007, 79, 993. (e) Bonneau,

R.; Liu, M. T. H. In Advances in Carbene Chemistry; ed.; Brinker, U. H., Ed.; JAI

Press: Stamford, CT, 1998; Vol. 2, p 1. (f) Toscano, J. P. In Advances in Carbene

Chemistry; ed.; Brinker, U. H., Ed. 1998; Vol. 2, p 215. (g) Jackson, J. E.; Platz, M.

S. In Advances in Carbene Chemistry; ed.; Brinker, U. H., Ed. 1994; Vol. 1, p 89.

(h) Kinetics and spectroscopy of carbenes and biradicals; Platz, M., Ed.; Plenum

Press: New York, 1990. 124

(4) Gaussian 16, Revision A.03, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,