LIGHT AS A REAGENT FOR CHEMICAL REACTIONS-EXCITED STATE MANIPULATION TO DISCOVER NEW REACTIVITY
Sunil Kumar Kandappa
A Dissertation
Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
December 2019
Committee:
Jayaraman Sivaguru, Advisor
Mihai Staic Graduate Faculty Representative
Malcolm Forbes
R. Marshall Wilson
© 2019
Sunil Kandappa
All Rights Reserved iii ABSTRACT
Photochemical reactions provide a complementary strategy for the synthesis of complex organic molecules as it often involves multiple bond formation in a single step. However, use of organic photoreaction as a common tool in synthesis is limited due to challenges associated with controlling their excited state properties. Altering the molecular framework has the potential to alter their excited state features opening new reactive pathways. This requires in depth understanding of reactivity and excited state dynamics. This dissertation details an effort to engineer new excited state reactions of organic molecules. Fundamentals of organic photochemistry and various strategies that were developed in this field are discussed in the first chapter. It details concepts related to organic photoreactions and asymmetric photochemical transformations, which are known to be quite challenging due to short life time and high energetics of the reactive excited states. The chapter details various methodologies that are developed and successfully implemented for controlling photochemical reactions. Second chapter describes photocycloaddition of an excited alkene to a carbonyl group. Due to the difference in the nature of orbital that initiates the cycloaddition, the reaction was labeled as Transposed Paternò-Büchi reaction. The strategy developed in this chapter is different from normal Paternò-Büchi, where an excited state carbonyl functionality adds to a ground state alkene. In-depth investigations were carried out to decipher the excited state in the reaction pathway with a likely mechanistic rationale. Chapter three details the photocycloaddition of excited alkenes with statistical and non- stabilized imines. This newly uncovered reaction was labeled as Aza Paternò-Büchi reaction. This new reaction was deciphered using photophysical studies. The reactive modes were analyzed by detailed mechanistic investigations. Fourth chapter details entropic effects as a tool to control chemoselectvity involving intramolecular [2+2] vs [3+2]-photocycloaddition. The physical properties for entropic control were deciphered due to [2+2] and [3+2] cycloaddition. iv
To my mom, dad, two little brothers and my wife v ACKNOWLEDGEMENTS
I would like to express my deepest appreciation and gratitude for the continuous support, help and guidance by my advisor Prof. Jayaraman Sivaguru, who was instrumental in shaping my Ph.D. career. He has been a great mentor for me and I learned a lot from him about organic photochemistry. His deep knowledge, long term vision, critical thinking, patience helped me for my professional development and to be a good scientist. He taught me the importance of hard work, integrity and perseverance for being successful in life. He always motivated me to set high standards in my professional world. I sincerely thank him again for this endless support.
I would like to extend my deepest gratitude to all my committee members at BGSU:
Prof. Malcolm Forbes, Prof. R. Marshal Wilson, graduate faculty representative Prof. Mihai
Staic for their support and guidance in keeping me in my Ph.D. track. I also want to thank all my committee members at NDSU: Prof. Mukund Sibi, Prof. Gregory Cook, Prof. Eakalak Khan for their invaluable support during my first three years of Ph.D. at NDSU.
Sivagroup has been always special place for me for my intellectual developments.
Critical discussions during group meeting or outside the group, friendly environment in the group really helped me to think independently. They were available for me whenever I need their help for any task in the lab. So, my special thanks to the present Sivagroup members:
Ravichandranath Singathi, Sapna Ahuja, Lakshmy Kannadi Valloli, Sruthy Baburaj, Sarvar
Aminovich Rakhimov, Seth Richard Smith and the past Sivagroup members: Dr. Anoklase
Ayitou, Dr. Barry Pemberton, Dr. Retheesh Krishnan, Dr. Elango Kumarasamy, Dr.
NandiniVallavoju, Dr. Ramya Raghunathan, Dr. Akila Iyer, Dr. AnthonyClay.
I would also like to thank all faculty members and staff members at the Centre for Pure and applied Photosciences at BGSU and at the Department of Chemistry and Biochemistry at
NDSU for their support and for being an inspiration with their work ethics. In particular, I want vi to thank Prof. Malcolm Forbe’s group, Prof. Pavel Anzenbacher’s group, Prof. Alexis
Ostrowski’s group, Prof. Joseph Furgal’s group at BGSU and Prof. Mukund Sibi’s group,
Prof. Gregory Cook’s group, Prof. Wenfang Sun’s group, Prof. Pinjing Zhao’s group at NDSU for their help in using the instruments and borrowing the chemicals from their lab in the time of need.
Special thanks to all my collaborators at Dr. Steffen Jockusch, Columbia University for the help in photophysical experiments and valuable intellectual discussions; Dr. Angel Ugrinov,
NDSU for the help and teaching me about single crystal XRD techniques; Prof. John Porco,
Boston University for his collaboration; Prof. Raghavan B. Sunoj, IIT Bombay, India for the help in computational experiments.
I would like to take this opportunity to thank Prof. Sridhar Rajaram, JNCASR,
Bangalore, India who was my mentor when I was working as a project assistant in JNCASR,
Bangalore. He was quite an inspiration who helped me to choose my Ph. D. carreer. He was a great teacher for me to get hold on fundamentals of organic chemistry and to learn many techniques in a synthetic chemistry lab. I also want to thank my former group members in
JNCASR Dr. Arjun, Dr. Raman and Dr. Debopreethi for their help and support.
I would like to extend my gratitude to the Centre for Photochemical Sciences and
Chemistry department, Bowling Green State university for the generous support with McMaster fellowship for my Ph.D. program. I would also like to thank NSF for funding support (CHE-
1213880, CHE-1465075, CHE-1811795).
I want to thank my mom, dad and brothers Rohith and Punith for their help and support during my Ph. D. time.
Finally, a very special thanks to my dear wife Arushi PV for her love, support and patience during my PhD time. vii
TABLE OF CONTENTS
Page
CHAPTER 1: INTRODUCTION TO LIGHT AS A REAGENT FOR CHEMICAL
REACTIONS – UNCOVERING NEW REACTIVITY FROM EXCITED STATES ...... 1
Introduction ...... 1
1.1 Interaction of light with matter ...... 2
1.1.1 Mechanism of light absorption ...... 2
1.1.2 Fundamental laws of photochemistry ...... 6
1.1.2.1 First law of photochemistry ...... 6
1.1.2.2 Second law of photochemistry ...... 6
1.1.2.3 Beer-Lambert law ...... 6
1.1.3 Absorption, emission and excitation spectra ...... 7
1.1.4 Franck-Condon principle ...... 9
1.1.5 Kasha’s rule ...... 9
1.2 Organic photochemistry ...... 11
1.2.1 Electron spin ...... 11
1.2.2 Jablonski diagram ...... 12
1.2.3 Chemiluminescence ...... 15
1.3 Experimental techniques for organic photochemical reactions ...... 16
1.3.1 Irradiation source ...... 16
1.3.2 Choice of solvents ...... 18
1.3.3 Reaction concentration...... 19
1.3.4 Effect of impurities ...... 19 viii
1.4 Sensitized photoreactions...... 19
1.4.1 Sensitization through energy transfer ...... 21
1.4.1.1 Energy transfer by electron exchange process or Dexter
mechanism ...... 21
1.4.1.2 Energy transfer by dipole-diploe interaction or Förster
mechanism ...... 22
1.4.2 Sensitization through electron transfer ...... 23
1.4.3 Marcus theory of electron transfer ...... 24
1.4.4 Stern – Volmer relationship ...... 28
1.5 Historical perspective of organic photochemical reactions ...... 29
1.5.1 Photoreaction of santonin ...... 29
1.5.2 Photodimerization reactions...... 30
1.6 Green chemistry through organic photochemical reactions – Giacomo
Ciamician (1857 – 1922) ...... 31
1.7 Some classic organic photochemical reactions ...... 34
1.7.1 Photocycloaddition reaction...... 34
1.7.2 Norrish Type I and Type II reaction ...... 35
1.7.3 Electrocyclic reaction...... 36
1.7.4 Sigmatropic rearrangement ...... 37
1.7.5 Di--methane rearrangement ...... 37
1.7.6 Photochemical ene reaction with singlet oxygen ...... 38
1.8 Chiral synthesis in organic photochemistry ...... 38
1.9 Photoredox mediated reaction for chiral induction ...... 41 ix
1.9.1 Light as a source of chirality ...... 42
1.9.2 Historical developments in photochemical asymmetric synthesis...... 44
1.9.2.1 Partial photodecomposition of racemic mixture ...... 44
1.9.2.2 Optical activation of racemic mixtures ...... 46
1.9.2.3 Asymmetric fixation ...... 47
1.10 Strategies for photochemical asymmetric synthesis ...... 48
1.10.1 Chiral auxiliary induced diastereoselectivity in [2+2]-
photocycloaddition reaction ...... 48
1.10.2 Chiral auxiliary induced diastereoselectivity in [4+2]-
photocycloaddition reaction ...... 52
1.10.3 Chiral auxiliary induced diastereomer equilibration ...... 53
1.10.4 Chiral complex induced rearrangement ...... 54
1.10.5 Photochemical asymmetric induction in crystalline media ...... 56
1.10.6 Photochemical asymmetric induction in supramolecular system ...... 59
1.11 Atropselective photoreactions - Photochemical asymmetric induction through
axially chiral chromophore ...... 64
1.11.1 Atropselective photoreactions ...... 68
1.12 Summary ...... 76
1.13 References ...... 76
CHAPTER 2: TRANSPOSED PATERNÒ-BÜCHI REACTION ...... 86
2.1 An overview of Paternò-Büchi reaction ...... 88
2.1.1 A generalized mechanism of a normal Paterò-Büchi reaction ...... 88
2.1.2 Site selectivity in Paterò-Büchi reaction ...... 93 x
2.1.3 Regioselectivity in Paterò-Büchi reaction ...... 94
2.1.4 Stereoselectivity in Paterò-Büchi reaction ...... 95
2.2 Transposed Paterò-Büchi reaction ...... 95
2.3 Evaluation of enamides for Transposed vs Normal Paterò-Büchi reaction ...... 99
2.4 Photophysical experiments ...... 104
2.4.1 Luminescence spectra ...... 105
2.4.2 Laser flash photolysis studies ...... 107
2.4.3 Deciphering the excited states in the Paterò-Büchi reaction of
substrates 156a-c from photophysical experiments ...... 110
2.5 Computational studies for Transposed vs normal Paterò-Büchi reaction ...... 111
2.6 Application of Transposed of Paterò-Büchi reaction ...... 113
2.7 Summary ...... 115
2.8 Experimental section ...... 115
2.8.1 General methods ...... 115
2.8.2 Computational methods ...... 117
2.8.3 Photophysical experiments ...... 118
2.8.4 Synthesis of tert-butyl-2,4,6-trimethylaniline carbamate ...... 118
2.8.5 Synthesis of tert-butyl 2,4-dimethyl-6-(tert-butylacetate)-N-
Boc-aniline 142 ...... 119
2.8.6 Synthesis of 2-amino-(3,5-dimethyl)-phenylethanol 150 ...... 124
2.8.7 Synthesis of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isopropyl)
ethanol 151 ...... 128
2.8.8 Synthesis of imide derivative 153 ...... 132 xi
2.8.9 Synthesis of imide derivative 154 ...... 136
2.8.10 Synthesis of alcohol derivative 155 ...... 140
2.8.11 Synthesis of aldehyde derivative 156a ...... 144
2.8.12 Computational studies of enamides ...... 154
2.8.13 Photophysical studies of enamides 134b-e,134g,148 ...... 160
2.8.14 Procedure for photoreaction of 156a...... 162
2.9 References ...... 165
CHAPTER 3: AZA PATERNÒ-BÜCHI REACTION...... 169
Introduction ...... 169
3.1 Excited state characteristics of imine double bond ...... 171
3.1.1 Photoisomerization ...... 171
3.1.2 Photoreduction ...... 172
3.1.3 Photoalkylation ...... 173
3.1.4 Photoelimination ...... 173
3.1.5 Photofragmentation ...... 174
3.1.6 [2+2]-Photocycloaddition of imines ...... 175
3.2 The case for Aza Paternò-Büchi reaction ...... 178
3.2.1 Synthesis of enamide imines for evaluating Aza Paternò-Büchi
reaction ...... 181
3.2.2 Determination of racemization barrier for atropisomeric imines ...... 183
3.2.3 Aza Paternò-Büchi reaction of atropisomeric imines ...... 187
3.2.4 Mechanistic investigations ...... 191
xii
3.2.4.1 Analysis of E/Z isomerization of atropisomeric imine 192a
during photoreaction ...... 191
3.2.4.2 Photophysical experiments ...... 194
3.2.4.3 XRD data for Aza Paternò-Büchi photoproducts 193c
and 193f ...... 197
3.2.5 Mechanistic rational for Aza Paternò-Buüchi reaction ...... 199
3.3 Summary ...... 200
3.4 Experimental section ...... 201
3.4.1 General methods ...... 201
3.4.2 Synthetic protocol for lactam aldehyde 198 ...... 204
3.4.3 Procedure for the synthesis of lactam imines and their precursors ...... 204
3.4.3.1 Synthesis of 1-(2-(2-((triisopropylsilyl)oxy)ethyl)phenyl)
pyrrolidin-2-one 196 ...... 204
3.4.3.2 Synthesis of 1-(2-(2-hydroxyethyl)phenyl)pyrrolidin-2-
one 197 ...... 209
3.4.3.3 Synthesis of 2-(2-(2-oxopyrrolidin-1-yl)phenyl)
acetaldehyde 198 ...... 213
3.4.4 Racemization kinetics for non-biaryl atropisomeric imines ...... 224
3.4.5 Photophysical studies of imine derivatives ...... 225
3.4.6 General irradiation procedure and characterization of imine
derivatives ...... 227
3.4.6.1 General irradiation procedure for the imine derivatives
192a-d,192g ...... 227 xiii
3.4.7 UV-Visible absorption spectra ...... 247
3.4.8 X-ray structural parameters...... 247
3.5 References ...... 250
CHAPTER 4: ENTROPIC CONTROL OF PHOTOCHEMICAL REACTION: A CASE
STUDY INVOLVING [3+2]-PHOTOCYCLOADDITION ...... 253
Introduction ...... 253
4.1 Temperature effect on photochemical reaction...... 253
4.1.1 General overview of Eyring equation ...... 253
4.1.2 Entropy control in a photochemical reaction ...... 255
4.2 [3+2]-Photocycloaddition reaction ...... 257
4.2.1 [3+2]-Photocycloaddition reaction of three membered rings ...... 257
4.2.2 Meta-cycloaddition reaction ...... 258
4.3 [3+2]- Photocycloaddition of phenylketone enamide 156b ...... 260
4.4 Conclusion ...... 270
4.5 Experimental section ...... 270
4.5.1 Synthetic protocol for 4-methoxy phenyl ketone derivative 220 ...... 271
4.5.2 General irradiation procedure and characterization of photoproducts .. 275
4.5.3 XRD data ...... 281
4.6 References ...... 282
CHAPTER: 5 CONCLUSIONS ...... 283 xiv
LIST OF CHARTS
Chart Page
1.1 Some common organic chromophores...... 9
1.2 Triplet energies (ET in kcal/mol) of some organic molecules ...... 21
1.3 Some typical organic photochemical reactions...... 34
2.1 Oxetane ring containing natural products/drugs ...... 87
2.2 Structure of enamides, its photoproduct and compounds used for its synthesis ...... 99
2.3 Compounds used for photophysical experiments ...... 105
2.4 Enamides and sensitizers employed for photophysical studies ...... 160
3.1 Structure of atropisomeric imines its photoproducts, substrates for photophysics
and the corresponding compounds used for their synthesis...... 180
3.2 Substrates and sensitizer employed for photophysical studies ...... 225
4.1 Compounds utilized for the study of temperature effect on [2+2] vs [3+2]
photocycloaddition and the precursors used for their synthesis ...... 261 xv
LIST OF EQUATIONS
Equation Page
1.1 Equation 1.1 ...... 2
1.2 Equation 1.2 ...... 3
1.3 Equation 1.3 ...... 6
1.4 Equation 1.4 ...... 7
1.5 Equation 1.5 ...... 7
1.6 Equation 1.6 ...... 11
1.7 Equation 1.7 ...... 12
1.8 Equation 1.8 ...... 23
1.9 Equation 1.9 ...... 23
1.10 Equation 1.10 ...... 25
1.11 Equation 1.11 ...... 27
1.12 Equation 1.12 ...... 28
1.13 Equation 1.13 ...... 28
1.14 Equation 1.14 ...... 29
1.15 Equation 1.15 ...... 39
1.16 Equation 1.16 ...... 43
1.17 Equation 1.17 ...... 44
1.18 Equation 1.18 ...... 44
2.1 Equation 2.1 ...... 102
3.1 Equation 3.1 ...... 184
3.2 Equation 3.2 ...... 185 xvi
3.3 Equation 3.3 ...... 185
3.4 Equation 3.4 ...... 185
3.5 Equation 3.5 ...... 185
3.6 Equation 3.6 ...... 185
3.7 Equation 3.7 ...... 186
4.1 Equation 4.1 ...... 253
4.2 Equation 4.2 ...... 254
4.3 Equation 4.3 ...... 254
4.4 Equation 4.4 ...... 254
4.5 Equation 4.5 ...... 254 xvii
LIST OF FIGURES
Figure Page
1.1 Electromagnetic spectrum ...... 2
1.2 Interaction of electric field and magnetic field of electromagnetic wave on electron 4
1.3 Interaction of electric field on hydrogen atom ...... 5
1.4 Light from light source LS, with incident light intensity 퐼o passing through a cuvette
of path length 푙 ...... 7
1.5 Spectral features in absorption spectra ...... 8
1.6 Potential energy diagram of ground and excited state for absorption process ...... 10
1.7 Global paradigm of organic photochemistry ...... 11
1.8 Jablonski diagram ...... 12
1.9 (a). Bioluminescence in fire fly (b). Bioluminescence in sea due to Noctiluca
Scintillans or sea sparkle ...... 15
1.10 (a). Ryonet reactor; (b-c). LED reactor (d). Compact fluorescent lamp ...... 18
1.11 Energy transfer through electron exchange interaction ...... 22
1.12 Energy transfer through dipole-dipole interaction ...... 23
1.13 Polar solvent molecule orientation around polar and nonpolar species during
electron transfer ...... 24
1.14 (a-d) The graph illustrating variation of potential energy with respect to reaction
co-ordinate ΔG0 for an electron transfer reaction. (e) Schematic plot of log ket vs
∆Get for an electron transfer reaction depicting Marcus normal region and Marcus
inverted region ...... 26
1.15 A schematic representation of [m+n]-photocycloaddition reaction...... 35 xviii
1.16 Potential energy diagram for asymmetric thermal vs photochemical reaction ...... 40
1.17 Photoredox catalyst employed for the reaction in Scheme 1.12 ...... 42
1.18 Schematic diagram for polarization of light ...... 43
1.19 and form of cinnamic acid crystal and the distance of separation of reacting
bond...... 57
1.20 Host guest interaction in supramolecular photocatalysis ...... 60
1.21 Schematic view of atropisomeric molecules and its designation a P and M isomers 65
1.22 Curan’s prochiral auxiliary model for asymmetric synthesis in thermal reaction ..... 67
1.23 A schematic diagram for NEER principle ...... 68
1.24 Substrate catalyst complex with substrate 119a and catalyst 121e ...... 74
2.1 Mechanism of a normal Paternò-Büchi reaction with an n* excited carbonyl
compound ...... 88
2.2 (a) Interaction of n* excited state of carbonyl group with ground state alkene
molecular orbit. (b) Interaction of * excited state of alkene chromophore with
ground state carbonyl group...... 90
2.3 Luminescence spectra of 156b, 156c, and 159 measured in ethanol glass measured
at 77K ...... 106
2.4 Stern-Volmer plot for the determination of bimolecular quenching rate constant for
the quenching of (a) xanthone triplet with various concentration of enamides 156d-e,
and 158 (b) thioxanthone triplet with various concentration of enamide 158 ...... 107
2.5 Stern-Volmer plot for the determination of bimolecular quenching rate constant
for the quenching of (a) xanthone triplet with various concentration of enamides
156b-c, and 159 ...... 109 xix
2.6 Schematic representation of traditional vs transposed Paternò-Büchi reaction ...... 111
2.7 Frontier molecular orbitals involved in the π enamide → π* triplet excited state of
156g and 156f ...... 112
2.8 1H-NMR of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149 ...... 121
2.9 13C-NMR of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149 ...... 122
2.10 HRMS of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149 ...... 123
2.11 1H-NMR of 2-amino-(3,5-dimethyl)-phenethylalcohol 150 ...... 125
2.12 13C-NMR of 2-amino-(3,5-dimethyl)-phenethylalcohol 150 ...... 126
2.13 HRMS of 2-amino-(3,5-dimethyl)-phenethylalcohol 150 ...... 127
2.14 1H-NMR of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151 ...... 129
2.15 13C-NMR of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151 ...... 130
2.16 HRMS of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151...... 131
2.17 1H NMR of imide derivative 153 ...... 133
2.18 13C-NMR of imide derivative 153 ...... 134
2.19 HRMS of imide derivative 153 ...... 135
2.20 1H-NMR of enamide derivative 154 ...... 137
2.21 13C-NMR of enamide derivative 154 ...... 138
2.22 HRMS of enamide derivative 154 ...... 139
2.23 1H-NMR of alcohol derivative 155 ...... 141
2.24 13C-NMR of alcohol derivative 155 ...... 142
2.25 HRMS of alcohol derivative 155 ...... 143
2.26 1H-NMR of aldehyde derivative 156a ...... 145
2.27 13C-NMR of aldehyde derivative 156a ...... 146 xx
2.28 HRMS of aldehyde derivative 156a ...... 147
2.29 1H-NMR spectra of 156b ...... 148
2.30 13C-NMR spectra of 156b ...... 149
2.31 HRMS of aldehyde derivative 156b ...... 150
2.32 1H-NMR spectra of 156c ...... 151
2.33 13C-NMR spectra of 156c ...... 152
2.34 HRMS of 156c ...... 153
2.35 Frontier molecular orbitals involved in the enamide* triplet excited state of
156g and 156f ...... 154
2.36 UV/Vissible spectrum of 156e,156d and 149 measured in MeCN ...... 161
2.37 1H-NMR of photoproduct 157a ...... 163
2.38 13C-NMR of photoproduct 157a ...... 164
3.1 Various pathways for photoreaction of imines ...... 170
3.2 Strategy for intramolecular [2+2]-photocycloaddition of imine double bond to
alkene double bond ...... 181
3.3 Schematic representation of racemization and enantiomerization process for
Atropisomer ...... 184
3.4 Single crystal XRD of 193c and 193d that showing the azetidine hydrogen in syn-
geometry ...... 190
3.5 Low temperature 1H-NMR spectra of furoic imine derivative 192a-E and 192a-Z
over the course of photoreaction ...... 192
3.6 Determination of bimolecular quenching constant kq for the quenching of
xanthone triplet with various with imine 192a, 192c, 192d, 192h, enamide 158 xxi
and lactam 196 ...... 196
3.7 XRD structure of photoproduct 193d and 193f ...... 198
3.8 Proposed Mechanism for Aza Paternò-Büchi reaction ...... 199
3.9 1H-NMR spectra of lactam derivative 196...... 206
3.10 13C-NMR spectra lactam derivative 196 ...... 207
3.11 HRMS of lactam derivative 196 ...... 208
3.12 1H-NMR spectra of lactam alcohol derivative 197 ...... 210
3.13 13C-NMR spectra of lactam alcohol derivative 197 ...... 211
3.14 HRMS of lactam alcohol derivative 197 ...... 212
3.15 1H-NMR spectra of pyrrolidinyl aldehyde derivative 198 ...... 214
3.16 13C-NMR spectra of pyrrolidinyl aldehyde derivative 198...... 215
3.17 HRMS of pyrrolidinyl aldehyde derivative 198 ...... 216
3.18 1H-NMR spectra of diphenylimine derivative 192c ...... 217
3.19 13C-NMR spectra for diphenylimine derivative 192c ...... 218
3.20 HRMS of diphenylimine derivative 192c ...... 219
3.21 1H-NMR spectra of benzyloxy imine derivative192e ...... 221
3.22 13C-NMR spectra of benzyloxy imine derivative192e ...... 222
3.23 HRMS of benzyloxy imine derivative 192e ...... 223
3.24 Racemization kinetics of atropisomeric imines 192 in acetonitrile at 50 ºC ...... 224
3.25 Determination of the bimolecular quenching rate constant kq of quenching of
xanthone triplet states by 196 using laser flash photolysis ...... 226
3.26 1H-NMR of spectra furoic hydrazide photoproduct 193a ...... 229
3.27 13C-NMR spectra of furoic hydrazide photoproduct193a ...... 230 xxii
3.28 HRMS for furoic hydrazide photoproduct 193a ...... 231
3.29 1H-NMR spectra for N,N-dimethylhydrazine photoproduct 193b ...... 233
3.30 13C NMR spectra for N,N-dimethylhydrazine photoproduct 193b ...... 234
3.31 HRMS spectra for N,N-dimethylhydrazine photoproduct 193b ...... 235
3.32 1H-NMR spectra for N,N-diphenylhydrazine photoproduct 193c ...... 237
3.33 13C-NMR spectra for N,N-diphenylhydrazine photoproduct 193c ...... 238
3.34 HRMS for N,N-diphenylhydrazine photoproduct 193c...... 239
3.35 1H-NMR spectra for morpholinehydrazine photoproduct193d ...... 241
3.36 13C-NMR spectra for morpholinimine photoproduct193d ...... 242
3.37 HRMS for morpholinimine photoproduct193d ...... 243
3.38 1H-NMR spectra for 193g ...... 245
3.39 13C-NMR of 193g ...... 246
3.40 UV-Vis absorption spectra ...... 247
3.41 XRD structure of photoproduct (a) 193c and (b) 193d ...... 249
4.1 1H-NMR spectra of 157b and 218 cycloadduct along with starting material of
phenylketone 156b ...... 264
4.2 Expanded region of crude reaction mixture NMR spectra depicting 157b and 218b
cycloadduct resonances of the bridge head protons “Ha” (in 157b) and “Hb” (in
218b) at different temperatures ...... 265
4.3 Eyring plots for [2+2] -photoproduct 157b vs [3+2]-photoproduct 218 at different
temperature in acetonitrile solvent ...... 267
4.4 1H-NMR spectra of 4-methoxy phenylketone derivative 156h ...... 273
4.5 13C-NMR spectra of 4-methoxy phenylketone derivative 156h ...... 274 xxiii
4.6 1H-NMR spectra of [2+2]-photocycloaddition product 157b ...... 277
4.7 13C-NMR spectra of [2+2]-photocycloaddition product 157b ...... 278
4.8 1H-NMR spectra of [3+2]-photocycloaddition product 218 ...... 279
4.9 13C-NMR spectra of [3+2]-photocycloaddition product 218 ...... 280
4.10 Single crystal XRD structure of [3+2]-photocycloaddition product 218...... 281 xxiv
LIST OF SCHEMES
Scheme Page
1.1 (a). Schematic representation of an organic photochemical reaction depicting
possible intermediates in the excited state and in the ground state. (b). Electronic
configuration and relative energies of electrons of intermediates ...... 14
1.2 Bioluminescent reaction in fire flies involving oxidation of D-luciferin (13) to
oxyluciferin (16) ...... 16
1.3 Electron transfer from photo excited species ...... 24
1.4 Photoreaction of santonin in solution (a) and solid state (b) ...... 30
1.5 [4+4]-Photodimerization of anthracene 10 to the dimer 37 ...... 30
1.6 Various organic reaction under mild photochemical condition (a – e) developed by
Giacomo Ciamician ...... 33
1.7 [2+2]-photocycloaddition reaction alkene 49 with C=X (X = CH2, O, S, NH)
double bond 50 ...... 35
1.8 Norrish Type I and Type II cleavage of simple ketones ...... 36
1.9 Electrocyclic reaction of 1,3,5 triene 52 to cyclohexadiene derivative 53 ...... 37
1.10 Sigmatropic rearrangement along a conjugated system ...... 37
1.11 Di- methane rearrangement of 1, 4 - diene 56 ...... 38
1.12 Photoene reaction involving singlet oxygen 59 and allylic system 58 ...... 38
1.13 Asymmetric alkylation of acycl imidazole derivative 61 by photoredox catalysis ... 41
1.14 Photochemical asymmetric induction by partial photodecomposition of racemic
mixture using circularly polarized light (CPI) ...... 45
1.15 Optical activation of trioxalate chromium (III) complex 68 in using cpl ...... 47 xxv
1.16 Photochemical asymmetric synthesis of hexahelicene using circularly polarized
light ...... 47
1.17 Diastereoselective [2+2]-photocycloaddition of stilbene 25 with chiral dialkyl
fumarate 71 ...... 50
1.18 Diastereoselective [2+2]-photocycloaddition of enone 74 with cyclopentene 75 ..... 52
1.19 Intramolecular [2+2]-photocycloaddition of 9-anthryl-fumarte ester 78...... 53
1.20 Diastereoselective photo equilibration by sensitization ...... 54
1.21 Chiral solvent mediated photochemical asymmetric induction for the conversion of
nitrone 81 to oxaziridine 83 ...... 56
1.22 Dimerization reaction of , and cinnamic acid (84a, 84b, and 84c) in crystalline
media ...... 58
1.23 Chiral induction through crystalline media for di--methane rearrangement ...... 59
1.24 Chiral induction in zeolites media for Norrish type II reaction of 87,
photocyclization of 89 and 91 ...... 61
1.25 Cyclodextrin mediated chiral induction in benzoin 94 formation from
benzaldehyde 93...... 63
1.26 Chiral template mediated photocycloaddition of coumarin derivative 96 ...... 64
1.27 Atropisomeric binaphthyl derived catalyst 102 in asymmetric Diels-Alder reaction
of benzaldehyde 93 and 1,4-butadiene derivative 99 ...... 66
1.28 Intramolecular atropselective radical cyclization of acryl anilide 103 ...... 67
1.29 6 - Photocyclization of atropisomeric acrylanilides 105 ...... 69
1.30 4 - ring closure of atropisomeric 2-pyridones 108 ...... 70 xxvi
1.31 Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric
acrylimides 110 ...... 71
1.32 Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric
3,4-dihydro-2-pyridones 113 ...... 72
1.33 Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric
maleimides 116 ...... 73
1.34 Organophotocatalysis with thiourea based hydrogen bonding catalyst 121 for
intramolecular [2+2] photocycloaddition in coumarin derivatives 119 ...... 75
2.1 Paternò-Büchi reaction of benzaldehyde 93 with alkene 121 ...... 87
2.2 Paternò-Büchi reaction of benzophenone 21 with cyclopropyl ethylene
derivative 131...... 91
2.3 Paternò-Büchi reaction from * excited state of carbonyl group of 134 with
alkene 135 ...... 92
2.4 Mechanism of a traditional Paternò-Büchi reaction involving photoinduced
electron transfer ...... 93
2.5 Site selective Paternò-Büchi reaction of benzaldehyde 93 with 2-methl furan 13 .... 94
2.6 Site selective Paternò-Büchi reaction of benzophenone 21 with 2-methyl furan 138 94
2.7 Regioselective Paternò-Büchi reaction of benzophenone 21 and uracil
derivative 140...... 94
2.8 Griesbeck model of 1,4-biradical in Paternò-Büchi reaction ...... 95
2.9 Diastereoselective Paternò-Büchi reaction controlled through Kemp’s triacid
derived chiral auxiliary ...... 96
2.10 Normal vs transposed Paternò-Büchi reaction ...... 96 xxvii
2.11 Normal vs transposed Paternò-Büchi reaction of five membered enamide
chromophore tethered with alkyl/aryl ketone ...... 98
2.12 General scheme for the synthesis of aldehyde 156a ...... 101
2.13 [2+2] vs competitive hydrogen abstraction product in Paternò-Büchi reaction ...... 114
2.14 A general representation of addition of excited alkene to any double bond ...... 114
2.15 Synthesis of tert-butyl-2,4,6-tert-butylcarbamate 148 ...... 118
2.16 Synthesis of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149 ...... 119
2.17 Synthesis of 2-amino-(3,5-dimethyl)-phenethylalcohol 150 ...... 124
2.18 Synthesis of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151...... 128
2.19 Synthesis of imide derivative 153 ...... 132
2.20 Synthesis of enamide derivative 154 ...... 136
2.21 Synthesis of alcohol derivative 155 ...... 140
2.22 Synthesis of aldehyde derivative 156a ...... 144
2.23 Synthesis of photoproduct 157a ...... 162
3.1 Imine [2+2] photocycloaddition vs alkene ...... 169
3.2 Schematic representation for the photoisomerization of imines ...... 171
3.3 Photoisomerization of N-(O-methyl) acetophenone oxime 160 ...... 171
3.4 syn – anti photoisomerization of N-(O-methyl)2-naphthol oxime 161 ...... 172
3.5 Photoreduction of benzophenone imine 162...... 172
3.6 Photoalkylation of indolene 165 ...... 173
3.7 Photoelimination of 2-alkylquinoline 168 ...... 174
3.8 -cleavage of cyclic imine derivatives 171 and 174 ...... 175
3.9 Imine [2+2]-photocycloaddition of 2,5-diphenyl-2,3-4-oxadiazole 177 ...... 176 xxviii
3.10 Imine [2+2]-photocycloaddition of 3-ethoxyisoindolone 180 ...... 176
3.11 Imine [2+2]-photocycloaddition of 3-ethoxyisoindolone ...... 177
3.12 Photoreaction of oxazinone derivative 186 ...... 177
3.13 Photoreaction of oxazinone derivative 189 by Sampedro and co-workers ...... 178
3.14 Synthesis of atropisomeric imines 192a-h ...... 182
3.15 Schematic representation for the racemization of atropisomeric imines ...... 186
3.16 Low temperature photoreaction of 192a under xanthone sensitization ...... 191
3.17 Room temperature photoreaction of 192h under xanthone sensitization...... 193
3.18 Low temperature photoreaction of 192e under xanthone sensitization ...... 194
3.19 Scheme for the synthesis of lactam aldehyde 198 ...... 204
3.20 Synthesis of TIPS pyrrolidinone derivative 196 ...... 204
3.21 Synthesis of hydroxyethylpyrolidinone derivative 197 ...... 209
3.22 Synthesis of pyrrolidinyl aldehyde derivative 198 ...... 213
3.23 General irradiation procedures for imine derivatives 192a-d, 192g ...... 227
4.1 Entropy controlled enantio differentiating isomerization of cyclooctene Z - 200
in the presence of bulky chiral sensitizer 201 and 202 ...... 256
4.2 Entropy controlled Paternò-Büchi reaction of cyclooctene in the presence of bulky
chiral sensitizer ...... 257
4.3 Three membered ring in [3+2] photocycloaddition ...... 258
4.4 Aziridine in [3+2]-photocycloaddition of aziridine 208 ...... 258
4.5 Meta-cycloaddition reaction ...... 259
4.6 Meta photocycloaddition in the synthesis of -cedrene 214 ...... 259
4.7 Meta photocycloaddition in the synthesis methyl rocaglate 217 ...... 260 xxix
4.8 Photoreaction of enamide 156b to form [2+2]-photoproduct 157b and [3+2]-
photoproduct 218 ...... 263
4.9 Photoreaction enamide 156h to form [2+2]-photoproduct 157h and [3+2] –
photoproduct 219 ...... 268
4.10 Plausible mechanism for the formation of [3+2]-photocycloaddition product 157b . 269
4.11 Grignard reaction for the synthesis of 4-methoxy phenylketone derivative 156h ..... 271
4.12 Photoreaction of phenylketone derivative 156b and 220 ...... 275 xxx
LIST OF TABLES
Table Page
1.1 Energy of electromagnetic radiations and types of interaction with matter ...... 5
1.2 Solvent cut-off wavelength ...... 18
1.3 Diastereomeric excess, relative quantum yield and emission maximum for the
exciplex formation for the reaction of stilbene with chiral dialkyl fumarate 71a-e... 51
1.4 Diastereoselectivity for photochemical asymmetric induction of nitrones with chiral
complexing solvent under various conditions ...... 56
2.1 Transposed vs normal Paternò-Büchi reaction of enamide substrate ...... 103
2.2 Vertical excitation energies (kcal/mol) of different transitions calculated at the cLR-
PCM(acetone)/TD-CAM-B3LYP/6-31+G* level of theory ...... 156
2.3 Frontier molecular orbitals involved in the lowest energy enamide* excited state
along with the major contributing transitions for 156d and 158 ...... 157
2.4 Frontier molecular orbitals involved in the lower energy excited state along with the
major contributing transitions for 140a-c, 140f ...... 158
2.5 Bimolecular quenching rate constant (kq) for the quenching of the sensitizer triplet
states by enamides...... 161
3.1 Imines 192a-d for atropselective photoreactions ...... 183
3.2 Activation energy, racemization rate constant and half-life for racemization of
optically pure atropisomeric imines 192a-d ...... 186
3.3 Atropselctive photoreaction of imines 192a-d ...... 188
3.4 Bimolecular quenching rate constant (kq) for the quenching of xanthone triplet
states by substrates ...... 226 xxxi
3.5 X-ray structural parameters of 193c-d, and 193f ...... 248
4.1 Effect of temperature on formation of 157b and 218 ...... 266
4.2 Effect of temperature on [2+2] vs [3+2] product formation (157b vs 218) in
toluene and DMF ...... 267
4.3 X-ray structural parameters of 218 ...... 281 xxx
LIST OF ABBREVATIONS c...... velocity of light e...... Electric charge eA...... electron acceptor eD...... electron donor
ET...... Triplet energies h...... Planks constant
HOMO...... highest unoccupied molecular orbital ket...... rate of electron transfer
LED...... Light emitting diodes
LUMO...... lowest unoccupied molecular orbital
S...... singlet state
T…...... Triplet state
Φ...... Quantum yield e...... ……………………………………………………………….…Molar extinction coefficient l...... Wavelength n...... Frequency
HRMS...... High Resolution Mass Spectroscopy
NMR...... Nuclear Magnetic Resonance
UV...... Ultra Violet
DMP...... Dess-Martin periodinane
DCM...... Dichloromethane
EtOAc...... Ethyl acetate xxxi
DMF...... Dimethylformamide ee...... Enantiomeric excess de...... Diastereomeric excess
AcOH...... Acetic acid
Boc...... t-Butyloxycarbonyl
M...... Molar min...... Minutes h...... Hour
Ph...... Phenyl rt...... Room temperature
TIPS...... Triisopropylsilyl mM...... Milli molar
Hex...... Hexane
CDCl3...... Dueterated chloroform
MeCN...... Acetonitrile
IPA...... Isopropyl alcohol
TLC...... Thin Layer Chromatography
Anhy...... Anhydrous
Satu...... Saturated 1
1 CHAPTER 1: INTRODUCTION TO LIGHT AS A REAGENT FOR CHEMICAL
REACTIONS – UNCOVERING NEW REACTIVITY FROM EXCITED STATES
Introduction
Light has a fundamental role to play for life sustenance on earth.1 Sun is the major source of energy in our solar system which are essential for life to thrive in our planet. It is believed that the light played a major role in the origin of life on earth.1,2 Light plays an seminal role in photosynthesis by plants, algae and some bacteria, where the light energy is converted to chemical energy through complex chemical reactions. Thus, the light mediated chemical reactions became an inseparable component of our everyday life. It also provided us with the gift of vision to see the world around us.3 Since sunlight is abundant, renewable, and eco-friendly in nature, it provides a gateway to overcome the present crisis for accessing clean energy by harvesting the power of photons. Several technological revolutions were possible because of light mediated processes in the fields of Physics, Chemistry, Biology, Electronics etc.4
Sunlight consists of a wide range of electromagnetic waves.5 An electromagnetic wave consists of oscillating electric and magnetic fields along the direction of propagation. An electromagnetic spectrum is the range of all wavelength/frequencies of an electromagnetic radiation. Sunlight reaching the earth’s surface consist of a spectrum of radiation ranging from gamma rays to radio waves. The visible light portion of electromagnetic spectrum which is accessible to the human eye and has a wavelength ranging from about 380 nm to 740 nm.
(Figure 1.1).
The light has dual nature, meaning that it has the behavior of both waves and particle.6 2
As a quantum particle, light features discrete packets of energy called photons. Energy of each photon is given by the Equation 1.1,
E = hn Equation 1.1 where h = Planks constant (6.626 ´ 10-34 m2kg/s), n = frequency of light (n = c/l; where c is velocity of light and l is its wavelength).
Figure 1.1: Electromagnetic spectrum. Adapted from reference 5.
1.1 Interaction of light with matter
1.1.1 Mechanism of light absorption7
Energy of UV-Visible radiation (l~ 200 -740 nm) are in the range corresponding to the outer electronic transition in atoms or molecules. In a classical view, electrons in an atom or molecule are viewed as an oscillating dipole which are localized in a molecular framework.
When a light of particular frequency falls on an atom and the frequency of the oscillating dipole moment matches with that of light, it leads to resonance resulting in the absorption of light. In other words, if the photon with specific energy matches with the energy required for electronic 3 transition in a molecule, it results in the absorption of photon for the respective electronic transition. The force imparted by the photon for the electronic transition is given by the equation
1.2.
�[��] � = �E + Equation 1.2 �
where e = electric charge; E = strength of electric field vector of the incident radiation; H = strength of magnetic field vector of the incident radiation; � = velocity of an electron; c =
8 -1 velocity of light. The velocity of an electron (�max ~ 10 cm s ) is relatively smaller than the velocity of light (c = 3 ´ 1010 cm s-1). So, the force due to magnetic field of electromagnetic radiation on electron is negligible compared to that of electric field (Figure 1.2).
For a hydrogen atom, light absorption can be viewed as follows. When wave function of
1s atomic orbital interacts with oscillating electric field vector E of an incident radiation, it causes electron cloud to move alternatively towards and away from electric field vector. This results p-atomic orbital with node at the center. This is termed as s ® p electronic transition
(Figure 1.3). 4
� �[��] H =
� = �E Magnetic vector Magnetic
Electric vector E
Propagation vector
Figure 1.2: Interaction of electric field and magnetic field of electromagnetic wave on electron.
Adapted from reference 7. 5
Electric vector of light wave
Direction of light wave +
Node
- Light + s orbital p-orbital
Figure 1.3: Interaction of electric field on hydrogen atom. Adapted from reference 7.
Different range of electromagnetic radiation can have different interactions with its atoms or molecules depending upon the energy of incident radiation and corresponding allowed transitions (Table 1.1).
Table 1.1: Energy of electromagnetic radiations and types of interaction with matter.8,9
Electromagnetic Range of energy (eV) Type of interaction radiation g-radiation ~ 1.2 ´ 107 - 1.2 ´ 105 Nuclear excitation X- radiation ~ 1 ´ 105 - 124 Inner electronic transition UV-Visible ~ 123 - 1.6 Outer electronic transition radiation IR- radiation 1.4 - 1.2 ´ 10-3 Molecular vibration Molecular rotation, Micro wave 1.2 ´ 10-3 - 1.2 ´ 10-6 Electron spin resonance Nuclear magnetic Radio wave 1.0 ´ 10-6 - 1.2 ´ 10-23 resonance 6
1.1.2 Fundamental laws of photochemistry8,9
1.1.2.1 First law of photochemistry
First law of photochemistry states that only the light which is absorbed by a system can cause chemical change. This is also called as Grotthus-Draper law.
1.1.2.2 Second law of photochemistry
According to second law of photochemistry one photon of light is absorbed per molecule of absorbing and reacting molecule. This is also called as Stark-Einstein law.
1.1.2.3 Beer-Lambert law
According to Lambert law, fraction of incident radiation absorbed by a transparent material is independent of the intensity of incident radiation and each successive layer absorbs a portion of incident radiation. Beer law states that amount of incident radiation is proportional to the number of molecules absorbing the incident radiation. So, as per Beer-Lambert law, for a light with incident intensity �o, passing through a cuvette of path length � (Figure 1.4), change in
intensity a C� where C is the concentration of light absorbing molecule in the cuvette and � is its length.
��� e � = C Equation 1.3
where e is, a constant called molar extinction coefficient. 7
�
�o �
LS
Figure 1.4: Light from light source LS, with incident light intensity �o passing through a cuvette of path length �. � is transmitted light.
The term eC� is also called as absorbance ‘A’. Plot of A vs wavelength gives absorption spectra. The term transmittance (T) accounts for the ability of material to transmit the light
(Equation 1.4).
� Percentage transmittance, %� = × 100 Equation 1.4 �
Combining the equation 1.3 and 1.4,
A = 2 − log %� Equation 1.5
1.1.3 Absorption, emission and excitation spectra7,8
Absorption spectra is the plot of absorption intensity vs wavelength. Plot of emission intensity vs wavelength is called emission spectra. Excitation spectra includes plot of intensity of emission at different wavelength of excitation. Intensity of excitation spectra at a given emission wavelength is proportional to the absorption at excitation wavelength. So, excitation and absorption spectra has similar spectral feature and typically overlaps with each other. 8
Spectral features in absorption spectra depends on the electronic and vibrational energy level in the molecule. An atom has very distinct energy levels. So, its absorption spectra will have discrete sharp lines. Molecular absorption spectra have distinct features compared to that of atomic spectra. Each electronic energy level consists of corresponding vibrational energy levels.
Transition from lower electronic energy level to the different vibrational levels of higher electronic energy level result in the continuous absorption spectra. However larger molecule has vibrational energy levels which are arranged so closely with each other resulting in broad absorption peak.
E A
l
E A
l
E A
l
Figure 1.5: Spectral features in absorption spectra. Adapted from reference 8.
9
Atoms or group of atoms in a molecule which are responsible for the absorption of light are called as chromophores.
O O S N N O N O N H
1 2 3 4 5 6 7 1,3-butadiene Ketone Enone Imine Diazo Thioketone Maleimide group O O
O O 8 9 10 11 12
Benzene Naphthalene Phenanthrene Quinone Anthraquinone
10 Chart 1.1: Some common organic chromophores.
1.1.4 Franck-Condon principle10,11
According to Franck-Condon principle electronic transition takes place without change in the position of nuclei in the molecule and its environment. As the mass of electron (9.1 ´ 10-31 kg) is much less than the nuclear mass, nuclear displacement during electronic transition would be negligible. This results in a situation where ground state energy surface and excited sate potential energy surface will have same nuclear co-ordinates upon electronic excitation (Figure
1.6).
1.1.5 Kasha’s rule10,11
According to Kasha’s rule luminescence happens only from the lowest excited state. So even if the excitation of molecule from ground state results in the transition to higher excited state, it relaxes to lowest excited state. This will be followed by luminescence from lowest 10 excited state to the ground state. So, the energy of emitted photon will be less than that of photon involved in the excitation of molecule from its ground state. This energy difference in energy is called Stoke’s shift.
(a) (b) Third excited state
Second excited state
First excited state
v = 3 v = 3 v = 2 v = 2 Ground state v = 1 v = 1 v = 0 v = 0
Excitation from ground state to higher level excited state En where n = 1,2,3 etc.
Relaxation from higher excited state to lowest excited state (E1)
Electronic energy level in each excited state En
Vibrational energy level (v1) in each excited state
Electronic energy level in each excited state E n
Figure 1.6: Potential energy diagram of ground and excited state for absorption process (v is the vibrational energy level. (a). Excitation process (b). Emission process.
11
1.2 Organic photochemistry10,11
Organic photochemistry involves study of interaction of light with organic molecules. It includes photochemistry (study of chemical change) and photophysics (study of physical charecteristics that includes electronic transition, absorption, emission of light etc.). A general paradigm of organic photochemistry can be represented as in Figure 1.7. Organic reactant R gets excited into R* upon irradiation. R* can take three pathways to give product P. 1) It can either form an intermediate I to give product P, 2) It can go through funnel F to give product P or 3) R* can form an intermediate I* or product P* in the excited state, which eventually form the product
P in the ground state.
Efficiency of a photochemical reaction can be expressed in terms of quantum yield (Φ) which is defined as the ratio of number of product molecules formed to the number of photons absorbed.
Number of product molecule formed Φ = Number of photons absorbed Equation 1.6
Figure 1.7: Global paradigm of organic photochemistry.
1.2.1 Electron spin10
In the excited state R*, the electron which underwent transition to higher electronic energy state can retain the spin as in the ground state or can undergo a spin flip.
For a system with two electrons, if the spins are paired with opposite spin, total spin
− n = + = 0. 12
+ If the electrons are unpaired with parallel spin, the total spin, n = + = 1.
The spin multiplicity ‘S’ is given by the equation 1.7,
S = 2n+1 Equation 1.7
If two electrons are paired, they will have opposite spin and the spin multiplicity S = 1 and it is called as singlet state. If the two electrons are unpaired they will have same spin and the spin multiplicity S = 3 which is called as triplet state.
1.2.2 Jablonski diagram11
Reactant in the excited state, R* can be in singlet state (S) or triplet state (T). Controlling the spin of excited state is of paramount importance in directing the reactivity. Jablonski diagram summarizes various photophysical processes during an electronic excitation (Figure 1.8).
S -Singlet state E T -Triplet state 3 3 1 Electronic excitation S2 T2 2 Fluorescence 1 6 3 Vibrational relaxation 5 4 Phosphorescence S 3 1 5 Intersystem crossing (ISC) 6 1 2 T1 4 6 Internal conversion (IC) 5 Vibrational energy level S 0 Electronic energy level
Figure 1.8: Jablonski diagram.11
The excited state, R* can relax to ground state via radiative as well as non-radiative processes. Radiative transition can wither be fluorescence or phosphorescence where the 13
relaxation process involves emission of light. Transition from singlet excited state S1 to ground state S0 with the emission of light is called fluorescence (Step 1 in Figure 1.9). Emission of light that involves transition from triplet excited state T1 to S0 the ground state is called phosphorescence (Step 4 in Figure 1.8). Non-radiative relaxation does not involve emission of light. Instead, excess energy will be lost through physical process such as vibrational or bond rotation. The energy from the excited state might also be dissipated to the solvent molecules.
Vibrational relaxation between different vibrational energy levels of an electronic energy level is termed as internal conversion (Step 3 in Figure 1.8). However, if the vibrational relaxation happens between the state of different multiplicity (singlet to triplet), it is termed as intersystem crossing (Step 5 in Figure 1.8).
Singlet state features an unpaired electron with opposite spin. However, as per Hund’s rule pairing of electron in an orbital of equal energy will not happen until each orbital is singly occupied. So, the electronic configuration with unpaired electron in an orbital of equal energy will be more stable compared to the one that has paired electron leaving an empty orbital. This implies that triplet state is more stable compared to the corresponding singlet state derived from the same electronic configuration.
A typical organic photoreaction is depicted in Scheme 1.1 where the reactant R (S0)
1 * (reactant in the singlet ground state) form R (S1) (reactant in the singlet excited state) which
3 * undergoes intersystem crossing to form R (T1) (reactant in the triplet excited state). This leads to the formation 3I(D) (triplet diradical in the ground state), which again undergoes intersystem
1 crossing to form I(D) (singlet diradical in the ground state) followed by formation of P (S0)
(product in the ground state). The energy gap between 1R* and 3R* is termed as singlet triplet gap that is determined by the configuration of excited state (np* or pp*). 14
1 * 1 R (S1) can also form I(D) or I(Z) which can result in the formation of product
(zwitterion intermediate) which result in the formation of product P (S0).
(a)
hν 1 * ISC 3 * R(S0) R (S1) R (T1)
I (Z)
ISC P(S ) 1 3 0 I(D) I(D)
(b)
1 1 (NB1) (NB2)
LUMO 3I(D) 1I(D)
HOMO or or
1 * 3 * R(S0) R (S1) R (T1) P(S0) 1 (NB1) 1 (NB1) 1 (NB2) 1 (NB2) 3 1 I(Z) I(Z)
Scheme 1.1: (a). Schematic representation of an organic photochemical reaction depicting possible intermediates in the excited state and in the ground state. (b). Electronic configuration and relative energies of electrons of intermediates.
15
1.2.3 Chemiluminescence11,12
Radiative emission can also happen due to chemical reaction which produces an excited state species that emits radiation typically in the UV/visible region. This is called as chemiluminescence. Chemiluminescence observed in some living organisms is called bioluminescence (Figure 1.9).
Figure 1.9: (a). Bioluminescence in fire fly adapted from ref.13 (b). Bioluminescence in sea due to Noctiluca Scintillans or sea sparkle. Adapted from reference14.
In fire flies, bioluminescence is produced due to the oxidation of D-luciferin (13) to oxyluciferin (16) in the presence of luciferase enzyme. The reaction involves formation of high energy dioxetane (15) which decomposes with the release of light to form oxyluciferin (16)
(Scheme 1.2).
16
O Luciferase, O CO H O N N 2 +2 N N AMP N N ATP, Mg O2 - AMP O HO S S HO S S HO S S 13 14 15
- CO2 - hν
N N O
HO S S 16
Scheme 1.2: Bioluminescent reaction in fire flies involving oxidation of D-luciferin (13) to oxyluciferin (16) .11
1.3 Experimental techniques for organic photochemical reactions15
1.3.1 Irradiation source
Selection of proper light source is important for conducting a successful photochemical reaction. Emission from an irradiation source should have a wavelength that can be absorbed by the reactant. So, before setting up the reaction, absorbance of reactant sample should be taken into an account to choose a proper irradiation source and wavelength.
Ideal source of light energy for a chemical reaction would be the visible light, which is in abundance, renewable and environmentally friendly in nature. However, not all organic molecules have absorption in the visible part of the electromagnetic spectrum. Also, intensity of sunlight is not uniform throughout the day and at different parts of the world. So, an alternate light source is essential. There are different light sources that are commercially available that can be employed for photochemical reactions. Some of the sources that are typically employed are detailed below. 17
Generally, Mercury vapor lamps are used as a common light source. It consists of a discharge tube filled with mercury vapor. When high energy electric current passes through the discharge tube, it excites mercury atoms. The excited mercury atoms relax to ground state with the emission of light. Wavelength of emitted light depends upon the pressure of the mercury vapor in the discharge tube and the amount of electricity passing through it. As the pressure of mercury vapors increases, the emission lines in the longer wavelength increases.
Low pressure mercury vapor lamps operate under 6-16 W and has intense line at 253.7 nm and moderate intense line at 185 nm. Medium pressure mercury vapor lamp which operates under 100-1000 W has intense lines at 313, 366, 405, and 550 nm and diminished lines at 253.7 and 185 nm. Usually for organic photochemical reactions, medium pressure mercury vapor lamps are used. These lamps become very hot during their operation and the heat generated might decompose the reactant. Hence, typically these lamps are placed inside a water-cooled jacket to dissipate the heat energy during illumination.
Low pressure mercury vapor lamps coated with phosphor can act as a source of different radiation wavelengths. UV light from mercury vapor excites phosphor which emits radiations in the region of 305, 350, 370, 420 nm. To ensure the uniform irradiation of light, a photochemical reaction is set up in a Rayonet reactor with Merry go around (Figure 1.10a).
Light emitting diodes (LED’s) can act as an excellent light source for photochemical reactions. LED strips are less expensive and are easy to handle. A typical setup used for photoreactions is shown in figures 1.10b and 1.10c which can be rolled around a transparent glass jar and used for irradiating a sample (Figures 1.10b, c). 18
a b c d
Figure 1.10: (a). Ryonet reactor; (b-c). LED reactor (d). Compact fluorescent lamp.
1.3.2 Choice of solvents
If the solvent is not acting as sensitizer (Section 1.2.5) then, it should have minimal absorption at the irradiation wavelength to avoid any inner filter effect. So, one should be aware of cut-off wavelength of the solvent (the wavelength below which solvent has more absorption) employed for the reaction. Table 1.2 gives a list of solvents with their respective cut-off wavelength.
Table 1.2: Solvent cut-off wavelength15
Cut-off Cut-off Solvent Solvent wavelength (nm) wavelength (nm) Acetonitrile 190 Dimethyl Sulfoxide 268 Pentane 190 Ethanol 205 Water 190 Pyridine 305 Cyclohexane 205 Methanol 205 Methanol 205 Ethanol 210 Ethanol 210 Triflouroacetic acid 210 Triflouroacetic acid 210 1,4-dioxane 215 1,4-dioxane 215 Ethyl acetate 256 19
1.3.3 Reaction concentration
From Beer-Lambert’s law (Equation 1.5), for a photochemical reaction sample in a cell
with absorbance (i.e. ��� ) of 1, percentage transmittance (i.e. ) is just 10%. This means, almost 90% of the incident light is being absorbed by the molecules on the wall of cuvette.
Therefore, at the concentration where absorbance A = 1, molecules which are deep inside the cuvette or inside a reaction vessel will not encounter enough light for the reaction to occur.
In order to avoid these issues, the concentration of solution should be adjusted in such a way that light is available for most of the molecules for absorption. Solution with an absorbance of 0.2 has a transmittance of 63%. At his concentration, most of the light can penetrate throughout the sample. Hence, usually reactions are carried out at a concentration where absorbance of sample is around 0.2 (i.e. A ~ 0.2) at the irradiation wavelength.
1.3.4 Effect of impurities
Photochemical processes are usually quite sensitive to impurities and/or additives.
Reactions which involves a triplet state can be quenched by dissolved oxygen in the solvent media. So, reaction should be carried out in oxygen free condition. Radical quencher like amine impurity can also quench photoreaction. Heavy metal impurities can influence intersystem crossing rates, and hence influence mechanism of a photochemical reactions. Competitive absorption from impurities can impact the reaction efficiency and outcome. So before initiating a photoreaction one should be make sure that, the reaction mixture is free of all impurities.
1.4 Sensitized photoreactions10,11,16
Photosensitizers can undergo electronic excitation and transfer the energy to other ground state molecule leading to its excitation. So, a triplet photosensitizer can generate triplet state 20 typically due to efficient intersystem crossing of a molecule which is in the ground state. It is very difficult to achieve a photoreaction if the reacting molecule doesn’t have absorption in the region of irradiation wavelength or if it has minimal absorption. Such issues can be avoided by photosensitization by employing an appropriate photosensitizer. For a molecule to be an efficient photosensitizer, either of the following conditions must be met successfully.
a) Photosensitizer should have absorption at irradiation wavelength.
b) Reacting molecule should have minimal or no absorption at the irradiation wavelength.
c) For an efficient triplet sensitizer, triplet energy of reacting molecule should be lower
than the triplet energy of photosensitizer. Singlet sensitization could be avoided by
having lower singlet energy of sensitizer compared to that of reacting molecule. Chart
1.12 depicts triplet energy (kcal/mol) of some organic molecules.
Sensitization of a reactant molecule can happen either through energy transfer or electron transfer. 21
O N N O NN N O
17 18 19 20 Acetone 1,3,5 - Triazine Pyrazine Xanthone
ET = 79.4 ET = 74.1 ET = 75.5 ET = 75.4
O O
N S
21 22 23 24
Energy Energy Benzophenone Thioxanthone Styrene Quinoline E = 63.3 ET = 69.2 T ET = 61.8 ET = 61.7
S
S
25 26 27 28 E - Stilbene Pyrene Thioxanthione Tetracene E = 39.6 ET = 49.3 T ET = 29.3 ET = 48.4
17 Chart 1.2: Triplet energies (ET in kcal/mol) of some organic molecules.
1.4.1 Sensitization through energy transfer
There two mechanisms by which energy transfer can occur. Energy transfer by electron exchange process and energy transfer by dipole-diploe interaction.
1.4.1.1 Energy transfer by electron exchange process or Dexter mechanism18,6
In this case LUMO (lowest unoccupied molecular orbital) of excited donor transfers electron to LUMO of acceptor leaving a hole in the donor (Figure 1.11). Simultaneous back electron transfer from HOMO (highest unoccupied molecular orbital) of acceptor to HOMO of 22 donor results in overall energy transfer from donor to acceptor. This leaves donor in the ground state and acceptor in the excited state.
For Dexter mechanism to be effective, interacting molecules should feature overlapping absorption (acceptor) and emission (donor) profiles with each other. Therefore, for such process to be effective, the reacting molecule should collide with each other.
LUMO Energy transfer
HOMO * * D A D A
Figure 1.11: Energy transfer through electron exchange interaction.
1.4.1.2 Energy transfer by dipole-diploe interaction or Förster mechanism19,6
Excited state of donor can be considered as an oscillating dipole which interacts with acceptor resulting in its electronic excitation (Figure 1.12). There is no electron exchange interaction in this mechanism. So, dipole-dipole interaction can happen through space around the reacting species. Orbital overlap is not required for this mechanism. But electronic redistribution in the excited state of a molecule should result in dipole character for this mechanism to be effective.
Electrostatic interaction energy between two diploes is directly proportional to the magnitude of two interacting dipoles and inversely proportional to the cube root of separation 23
10 distance between the diploes (Equation 1.8). The rate constant of energy transfer kET is inversely proportional to the sixth power of donor-acceptor separation distance (Equation 1.9)
� � � (������ − ������) ∝ Equation 1.8 � � � � = Equation 1.9 �
where � and � are the dipole moments of donor and acceptor � is the distance of separation between donor and acceptor.
Typically for triplet energy transfer, the total spin angular momentum should be maintained and hence the energy transfer proceeds through electron exchange or Dexter mechanism while energy transfer from singlet state occurs through diploe-dipole or Förster mechanism.
Dipole
interaction-dipole Energy -dipole transfer Dipole interaction
* * D A D A
Figure 1.12: Energy transfer through dipole-dipole interaction.10
1.4.2 Sensitization through electron transfer10
Excited state of a sensitizer can transfer or accept an electron from the reactant.
Consequently, depending upon the redox potential of excited species it can either act as an 24 oxidant (electron acceptor or eA) or reductant (electron donor or eD) of reactant molecule. This results in an intermediate ‘I’ is known as radical ion pair (Scheme 1.3).
A*(eA)+ B(eD) I(A ,B )
A*(eD) B(eA) + I(A ,B )
Scheme 1.3: Electron transfer from photo excited species.
1.4.3 Marcus theory of electron transfer 20–22
For an efficient electron transfer process, solvent reorganization around the reacting molecule is critical. Solvent reorganization enables stabilization of intermediates formed due to electron transfer form one species to another. If a polar intermediate is formed in a polar solvent, solvent molecule would orient themselves to stabilize the intermediate. In non-polar solvent, a polar intermediate will be surrounded by randomly oriented solvent molecules (Figure 1.13). As electron transfer (Scheme 1.3) generates polar intermediates, typically polar solvents are employed for electron transfer reactions.
Electron transfer + + B A B A
= Solvent molecule
Figure 1.13: Polar solvent molecule orientation around polar and nonpolar species during electron transfer. 25
Marcus theory gives quantitative relationship between the free energy of activation and free energy for an electron transfer reaction. According to Marcus theory, electron transfer reaction involves solvent reorganization energy (l) which is the energy corresponding to vertical transition from reactant curve to product curve in the potential energy diagram (where nuclear motion is considered like a simple harmonic oscillator). In a photochemical reaction, this energy corresponds to the energy of photon involved in the excitation of molecule.
According to Marcus theory free energy of activation Δ�‡ is given by the Equation 1.10.
(Δ� + �) Δ�‡ = Equation 1.10 4�
where Δ� is standard free energy of reaction.
Case (a) in Figure 1.14 shows potential energy diagram when Δ� = 0, with solvent reorganization energy l. In this case, free energy of activation, Δ�‡ = �/4.
When reaction becomes exergonic, i.e when Δ� < 0, l decreases (Figure 1.14, b). So free energy of activation also decreases.
As reaction becomes more exergonic (Δ� ≪ 0), it reaches a point where free energy of activation Δ�‡ becomes zero. In this case, free energy of reaction Δ� = - l (Figure 1.14, c) where the rate of electron transfer is maximum.
When reaction becomes even more exergonic (Figure 1.14, d), Δ� > l, so free energy of activation Δ�‡ starts to increase decreasing the rate of electron transfer. 26
(a) (b)
l l 0 0 DG = 0 - DG < 0 A A A Potential energy Potential energy Reaction co-ordinate A Reaction co-ordinate
(c) (d)
l 0 0 A DG = - l A - DG << 0
Potential energy l Potential energy
A A Reaction co-ordinate Reaction co-ordinate
l = ΔG˚ (e)
et k
log Marcus Marcus normal inverted region region
- ΔG˚
Figure 1.14: (a-d) The graph illustrating variation of potential energy with respect to reaction
co-ordinate Δ� for an electron transfer reaction. (e) Schematic plot of log ket vs ∆Get for an electron transfer reaction depicting Marcus normal region and Marcus inverted region.
27
According to Marcus theory, rate of electron transfer reaction increases as reaction becomes more exergonic. However, as the reaction becomes more and more exergonic, reaction rate starts to decrease.
Figure 1.14 (e) shows plot of log ket (where ket is rate of electron transfer) vs free energy
° of electron transfer reaction (∆Get ). The region where rate of electron transfer decreases as exergonicity of reaction increases is called Marcus inverted region. The region where rate of electron transfer is less exergonic is called Marcus normal region.
In most of the cases, rate of electron transfer for photochemical reaction is very high.
According to electron exchange mechanism, for an electron transfer to occur, the reacting species must collide with each other. In solution phase, maximum rate that could be achieved for collision would be the rate of diffusion (~1010M-1S-1). So even if the free energy change of reaction is more negative and the rate of reaction is diffusion limited, Marcus inverted region cannot be achieved for a bimolecular reaction with diffusion being the rate limiting step.
Free energy of electron transfer reaction can be computed from Rehm-Weller equation
(Equation 1.11).23
∆Get = Eox (D) – Ered (A) – Eexe (A) – ∆E (Coloumbic) Equation 1.11 where,
∆Get = Free energy of electron transfer reaction
Eox (D) = Oxidation half-potential of donor
Ered (A)= Reduction half-potential of donor
Eexe (A)= Electronic excitation energy of acceptor 28
∆E (Coloumbic) = Couloumbic stabilization energy experienced by the oppositely charged ions generated after electron transfer in a given solvent
∆E (Coloumbic) = � Equation 1.12 where,
� = Avagadro’ number
� = Electron charge
� = Permittivity in vacuum
� = Dielectric constant of the solvent
� = Distance of separation of oppositely charged ions
1.4.4 Stern – Volmer relationship10
Efficiency of sensitization can be experimentally determined. When a sensitizer in the excited state (S)* transfers energy to another reacting species (R) and returns to ground state, then the sensitizer is said to be quenched with reactant acting as a quencher. The quenching process is a bimolecular reaction as shown below.
S* + R S+ R*
Efficiency of quenching or sensitization can be determined in terms of the rate constant of quenching kq. using the Stern-Volmer equation (Equation 1.13).
1 According to Stern-Volmer relationship, = � + � [�] Equation 1.13 � where,
� = Lifetime of excited state of reactant (sensitizer) in the presence of quencher 29
� = Rate constant of deactivation of reactant (sensitizer) in the absence of quencher
� = Rate constant of deactivation of reactant (sensitizer) in the presence of quencher
[�] = Concentration of quencher
Plot of vs [�] would be a straight line with a slope � which is the rate constant of quenching.
In terms of fluorescence intensity, Stern-Volmer equation can be written as equation 1.14.
� = 1 + �[�] Equation 1.14 �
where, � = Fluorescence intensity in the absence of quencher, � = Fluorescence intensity in the presence of quencher, � = Stern-Volmer quenching constant and K = � �
1.5 Historical perspective of organic photochemical reactions
1.5.1 Photoreaction of santonin
Earlier reports on the interaction of light with organic molecule goes back to 19th century.
In 1834 Hermann Trommsdorff24 reported about santonin crystal turning yellow and bursting upon exposure to sunlight. Later Sestini and Canizzaro reported that when a-santonin 29 was irradiated in aqu. ethanol it forms photosantonic acid 32 (Scheme 1.4).25 The structure of photosantonic acid was determined in 195826 and the structure of intermediates (30 and 31) were determined in 1963.27 Matsuura et.al reported the mechanism for solid state reaction of santonin.28 Solid state reaction involves sequential [4+2] dimerization of intermediate 35 followed by [2+2] cycloaddition to form cycloadduct 36 (Scheme 1.4). 30
(a) O O hν hν hν O HOOC O O O O 32 29 O 30 O 31 O O
- Santonin α Lumisantonin Mazdasantonin Photosantonic acid
(b) O O O hν hν O 4 + 2 hν π π 2π + 2π O O O O O O O O O O O O O O
33 34 35 36
α - Santonin [4+2] - adduct [2+2] - adduct
Scheme 1.4: Photoreaction of santonin in solution (a) and solid state (b).
1.5.2 Photodimerization reactions
Anthracene [4+4]-photodimerization is one of the earlier reports in organophotochemical transformations. In 1867 Fritzsche discovered that irradiation of anthracene 10 under sunlight results in the formation of some crystalline solid.25 Later, Elbs reported that the crystalline compound formed was its dimer 37 by molecular weight determination (Scheme 1.5). Linebarger confirmed the product 37 by its X-ray crystal structure.29
hν
10 37
Scheme 1.5: [4+4]-Photodimerization of anthracene 10 to the dimer 37. 31
1.6 Green chemistry through organic photochemical reactions –
Giacomo Ciamician (1857 – 1922)32
Concept of green chemistry involves chemical transformation using eco-friendly conditions such as use of safer reagent, design of chemical reactions with minimal waste byproducts, using renewable energy source and feed stock etc.33 In a photochemical reaction, photons as such can be considered as a reagent, since they lead to chemical change by their interaction with reactants. Therefore, a photochemical reaction can be considered as a greenest route for synthesizing molecules.34 Photons are inexpensive, renewable, and safer to handle
(especially when sunlight is used as energy source). The idea of using photochemical reactions as a means for safer and environmentally friendly way of synthesis was first proposed by
Giacomo Ciamician in the early 20th century (1908).32,35 He developed several photochemical strategies for some organic reactions which are milder compared to traditional thermal reactions.35
Ciamician showed C - C bond formation by alkylation of ketone 17 in the presence of methanol 38 as an alkylating agent under photochemical condition (Equation (a) in Scheme 1.6).
Such bond formation under thermal method involve generation of enolates which attacks carbonyl center. Generation of enolate ions is usually carried out under harsh conditions such as in the presence of strong base.
He also demonstrated oxidative dimerization of ketone 40 under photochemical condition
(Equation (b) in Scheme 1.6). Such reaction provides access to diketone 42 which can be eventually converted into heterocyclic compound after treating with suitable reagent. In this example pyrrole derivative 43 was synthesized after condensing diketone 42 with ammonia. 32
In Ciamician’s pioneering work with carvone 44, intramolecular [2+2] photocycloaddition was achieved to form carvonecamphor 45 (Equation (c) in Scheme 1.6). This reaction provided access to complex bicyclic system with multiple stereocentres in a single step.
Such a feature of photochemical reactions where multiple bond formation can take place in a single step can be very useful in the synthesis of complex natural products.
Ciamician also showed C - C bond cleavage of cyclic ketones under photochemical condition (Equation (d) in Scheme 1.6) to form open chain aldehyde 47 or carboxylic acid 48.
Under thermal conditions it requires harsh conditions such as use of KMnO4 and high temperature. 33
(a). C - C bond formation by alkylation of ketone
O hν H3C CH2OH + CH3OH (1) CH CH 3 3 H3C OH 17 38 39
(b). C - C bond formation by oxidative dimerization of ketone
H C CH H C CH O OH 3 3 3 3 hν NH + 3 (2) CH3 H3C CH3 CH H C 3 3 CH3 H3C N CH3 O O H 40 41 42 43
(c). Intramolecular [2+2] - photocycloaddition of carvone 35
O hν O (3)
44 45
(d). C - C bond cleavage of cyclic ketone under mild condition.
CHO
hν 1 O 1 2 2 R 1 R = i Pr, R = Me R R 47 (4) R2 CO2H 46 hν R1 = i Pr, R2 = Me R1 R2 O 2 48 O
Scheme 1.6: Various organic reaction under mild photochemical condition (a – e) developed by
Giacomo Ciamician.35 34
1.7 Some classic organic photochemical reactions
Some typical organic photochemical reactions are listed in the Chart 1.3.
Chart 1.3: Some typical organic photochemical reactions.
1.7.1 Photocycloaddition reaction
Photocycloaddition reactions involve addition of two multiple bonds to form a cyclic adduct. Figure 1.15 shows schematic representation of photocycloaddition of two reacting units where ‘m’ and ‘n’ represents number of p electrons involved in the reaction. Such reactions are synthetically quite beneficial as the it involves multiple bond formation in a single step. Small strained ring such as cyclobutane 51a,36 oxetane 51b (four membered ring with an oxygen atom),37 azetidine 51d (four membered ring with a nitrogen atom),38 thietanes 51c (four 35 membered ring with sulphur atom)39 can be synthesized by [2+2]-photocycloaddition reaction
(Scheme 1.7).
hν
m n m+n cycloaddition product
Figure 1.15: A schematic representation of [m+n]-photocycloaddition reaction.
X hν X +
49 50 51
X = CH2, O, S, NH
CH2 O S NH
Cyclobutane Oxetane Thietane Azetidine X = CH2 X = O X = S X = NH 51a 51b 51c 51d
Scheme 1.7: [2+2]-photocycloaddition reaction alkene 49 with C=X (X = CH2, O, S, NH) double bond 50.
1.7.2 Norrish Type I and Type II reaction40–42
Norrish Type I reaction involve homolytic cleavage of � bond (bond ‘a’ in Scheme 1.8) to the carbonyl group. Radical formed can further undergo homocoupling or disprportionation to form stable product. Stability of radical intermediate formed essentially determines the feasibility of Norrish Type I reaction (Scheme 1.8).
Carbonyl compounds with �- hydrogen can undergo Norrish Type II reaction (Scheme
1.8). It involves abstraction of hydrogen at �-position by carbonyl oxygen resulting in the 36 formation of 1,4-biradical. The 1,4-biradical can undergo cyclization to form cyclobutanol, called as Yang cyclization, or it can further undergo cleavage to form corresponding alkenes.
H Disproportio- O nation H R1 H O R2
R1 Radical O 2 R2 coupling R hν R1 R1 Type ! O R2 b H cleavage (a) O O R1 R1 a R2 R2 hν cleavageType (b) !! Radical cleavage OH R1 OH R2 1 R Yang HO 1 R2 cyclization R
R2
Scheme 1.8: Norrish Type I and Type II cleavage of simple ketones.
1.7.3 Electrocyclic reaction43
In an electrocyclic ring closure reaction, an open chain system with conjugated double bond (such as 52) undergo ring closure to form a cyclic scaffold (as in 53). The net result is that one p bond is converted to a � bond (Scheme 1.9). In an electrocyclic ring opening reaction a cyclic adduct transforms into an open chain compound where the transformation involves net conversion of one � bond into a p bond (Scheme 1.9). 37
hν Electrocyclic ring clossure
Electrocyclic ring opening
52 53
Scheme 1.9: Electrocyclic reaction of 1,3,5 triene 52 to cyclohexadiene derivative 53.
1.7.4 Sigmatropic rearrangement44
Sigmatropic reaction involves migration of group of atoms from one position of a conjugated skeleton to another position along a conjugated p system (Scheme 1.10). Atom or group of atoms undergoing migration involve hydrogen atom or carbon with its substituents. In the later case it is also termed as group migration.
hν G G
54 55 G = H atom or carbonyl group
Scheme 1.10: Sigmatropic rearrangement along a conjugated p system.
1.7.5 Di-p-methane rearrangement
The 1,4 diene of the type 56 with sp3 carbon at 3rd position undergo rearrangement as shown in the Scheme 1.11 to give cyclopropane derivative. Such reactions are called di-p- methane rearrangement or Zimmerman di-p methane reaction. 45 38
hν Ph Ph Ph Ph Ph Ph Ph Ph 56 57
Scheme 1.11: Di-p methane rearrangement of 1, 4 - diene 56.
1.7.6 Photochemical ene reaction with singlet oxygen
Photochemical ene reaction with singlet oxygen46 involve reaction between singlet oxygen 59 and an alkene with allylic hydrogen 58 (Scheme1.12). Oxygen abstracts allylic hydrogen with the migration of C=C double bond to the allylic position. This reaction is know as
Schenck ene-reaction. Singlet oxygen can also add to double leading to the formation of dioxetanes.83
O hν H O O HO
58 59 60
Scheme 1.12: Photoene reaction involving singlet oxygen 59 and allylic system 58.
1.8 Chiral synthesis in organic photochemistry
Chiral molecules lack center of symmetry and inversion symmetry. For every chiral molecule, there will be another molecule, which is its non-superimposable mirror image called an enantiomer. Even though a pair of enantiomer can have same physical properties, in a chiral environment, each of them can exhibit entirely different chemical, physical and biological properties. Most of the biological molecules (e.g. amino acids, sugars etc.) and life-saving drug molecules features at least one chiral center. In this regard, separation of pure enantiomer from a 39 mixture of enantiomers (racemic mixture) is of utmost importance in organic synthesis.47 Several techniques have been developed, where the reaction yield only one chiral compounds bypassing the other one. The strategy employed to access one enantiomer is called as enantioselective synthesis. In general strategies to access single stereoisomer (enantiomer or diastereomer) is called asymmetric synthesis.
Chirality in a molecule can be due to an atom typically carbon with four different substituents. This chiral atom termed as point chiral center. The enantiomer of point chiral center is labeled as ‘R’ and ‘S’ isomers.
The chirality of a molecule can also arise due to the restricted bond rotation along an axis called axial chirality. Each of the enantiomer in an axially chiral molecule are labelled as P and
M isomer.
Mixture containing 1:1 ratio of enantiomers is called as racemic mixture. Optical purity of a mixture of enantiomer is expressed using enantiomeric excess (ee) given by,
� − � % �� = � + � Equation 1.15 where � and � represents number of moles of R and S enantiomer respectively. The ratio of enantiomer is called as enantiomeric ratio (e.r).
Molecule featuring more than one chiral center can form non-superimposable non-mirror image called diastereomers. Similar to % ee, the excess of one diastereomer over another is termed as % diastereomeric ratio excess or diastereomeric ratio (dr).
Asymmetric synthesis has been the cornerstone of synthetic organic chemistry because of ever growing importance of chiral compounds in various industries. Strategies for asymmetric 40 synthesis in thermal reaction are very well established. It involves design of chiral catalyst(s) that can bind with reacting molecules(s) to influence the formation of a single stereoisomer. These reactions typically proceed through a diastereomeric transition state. The difference in free energy of activation between the diastereomeric transition states called differential activation energy (∆∆G‡) that determines the enhancement of one stereo isomer over the other (Figure
1.16).
R* (b)
(a)
ΔΔG‡ ΔΔG‡ R – Reactant R* – Reactant in the excited state P – Product ΔΔG‡ – Differential activation energy
R R P P (no selectivity) (enantioenriched)
Figure 1.16: Potential energy diagram for asymmetric thermal vs photochemical reaction.
While there are various strategies available to differentiate the diastereomeric transition state in thermal reaction, such strategies cannot be translated to photochemical reactions.48 This is because, the electronic excited state energy in a photochemical reactions is much higher than the energy corresponding to the diastereomeric transition state of a thermal reaction. Hence, excited state of a product transformation becomes a downhill process and distinction between the energy of diastereomeric transition states becomes challenging. Therefore, achieving stereoisomeric enhancement becomes challenging. 41
Thus, the photochemical asymmetric synthesis requires different approach than the one developed for thermal reactions.
1.9 Photoredox mediated reaction for chiral induction
Recently there has been increasing trend in photoredox mediated catalysis for asymmetric synthesis.49 These reactions involve metal based catalyst which undergo oxidation/reduction process under photochemical condition depending on the excited state redox potential of catalyst with respect to that of substrate which is in the ground state. However, in such reactions chiral induction happens in the ground state of substrate. Such reactions follow typical pattern of diasteroslective transition state as in thermal asymmetric reaction. Efficiency of chiral induction depends upon the differential activation energy of transition state.
Reaction in Scheme 1.13 is a prototypical example for organophotoredox catalysis reaction reported by Meggers and coworkers.50 Reaction involves visible light mediated asymmetric alkylation of acyl imidazole derivative 61 in the presence of chiral iridium catalyst
64a or 64b (Figure 1.17) with high enantiomeric excess. Iridium catalyst acts both as photoredox sensitizer and source of chiral induction.
CN O CN O N N Br !-Ir 64a or !-Ir 64b N Ph N Ph Vissible light NO2 MeOH, rt NO2
61 62 63
Scheme 1.13: Asymmetric alkylation of acycl imidazole derivative 61 by photoredox catalysis. 42
PF6 X tBu
N Me C N Ir N C Me X tBu
N
!-Ir 64a (X=O), !-Ir 65b (X=S)
Figure 1.17: Photoredox catalyst employed for the reaction in Scheme 1.13.
1.9.1 Light as a source of chirality
A non-polarized light has electric and magnetic field that are perpendicular with respect to each other and to each other along the direction of its propagation. If the oscillation of electric field vector is restricted to a plane with respect to the direction of propagation of light, then the light is called as plane polarized or linearly polarized light (Figure 1.18 c). In circularly polarized light, oscillation of electric field vector transcribes the shape of circle in all planes perpendicular to the direction of propagation (Figure 1.18 d). 43
(c)
(a) (b)
(d)
Figure 1.18: Schematic diagram for polarization of light. (a). Non-polarized light. (b). Polarizer.
(c). Linearly polarized light. (d) Circularly polarized light.
Therefore, light can be right circularly polarized (r-cpl) or left circularly polarized (l-cpl) based on whether the electric field vector rotates in right hand or left hand direction. Chiral molecules can have different absorption coefficient for r-cpl and l-cpl. These differential interactions can be measured by ORD (optical rotatory dispersion) or CD (circular dichroism) techniques. In ORD, differential refractive indices (∆� ) measured at a given wavelength is given by,
∆� = � − � Equation 1.16
where � and � are the refractive indices of left and right circularly polarized light.
Circular dichroism involves measure of differential absorption coefficients (∆�) with right and left circularly polarized light. 44
∆� = � − � Equation 1.17
where � and � are the absorption coefficients of left and right circularly polarized light.
Optical activity can also be measured using anisotropy factor or g factor given by,
∆�/� � = g = , where Equation 1.18
In a light induced chemical reaction, differential interaction of right and left circularly polarized light with the reacting molecule can be used as a source of chiral induction. The higher difference in absorption towards either r-cpl or l-cpl, higher chiral induction can be expected.
Chiral induction in photochemical reaction with circularly polarized light is also termed as absolute asymmetric synthesis.
1.9.2 Historical developments in photochemical asymmetric synthesis
Van’t Hoff (1874) and Le Bel (1894) proposed the idea of using circularly polarized light for photochemical asymmetric synthesis. Photochemical asymmetric synthesis with circularly polarized light can happen in three different ways such as (a) Partial photodecomposition of racemic mixture, (b) Optical activation of racemic mixtures, (c) Asymmetric fixation (vide infra).
1.9.2.1 Partial photodecomposition of racemic mixture:
In asymmetric induction by partial decomposition of racemic mixture, one of isomer reacts faster than the other one to form product leaving behind unreacted isomers. Monitoring the reaction with time will show increased optical activity due to unreacted starting material. Higher the extent of reaction, higher the expected optical activity. 45
Van’t Hoff and Le Bel51 proposed the idea of using circularly polarized light for photochemical asymmetric synthesis. This concept was later proved by Kuhn and co-workers
(1929)51. They irradiated solution of the racemic mixture of a-azido propionamide 66 in hexane using circularly polarized light to get 0.5 % ee after 40 % conversion (Scheme 1.14, equation 1).
The isomer, which has higher extinction coefficient towards circularly polarized light, reacts faster leading to its decomposition with the exclusion of nitrogen from the reaction. With the progress of time, concentration of other isomer (which has lower absorption) increases. For a quantitative chemical yield of optically active isomer, such reaction should be stopped before
100% conversion of all the starting material. Kagan and coworker also showed the photodecomposition of racemic mixture of solution of camphor 67 in hexane to get 20 % ee after
99 % completion of reaction (Scheme 1.13).52
O cpl O CH CH CH3 CH3 (1) 3 N 3 40 % conversion N N N3 CH3 3 CH3
66 66 Racemic Enantio enriched mixture mixture ee = 0.5 %
cpl (2) 99 % conversion O O 67 67 Racemic Enantio enriched mixture mixture ee = 20 %
Scheme 1.14: Photochemical asymmetric induction by partial photodecomposition of racemic mixture using circularly polarized light (CPI). 46
1.9.2.2 Optical activation of racemic mixtures
In this method, irradiation of racemic mixture with circularly polarized light results in the photo-equilibration of R and S isomers;
kr R S ks
where kr and ks are the rate constant for forward and reverse reactions respectively. kr and ks are proportional to the absorption coefficient of R and S isomer towards circularly polarized light.
For this method to be effective, rate of product formation should be slower than rate of equilibration.
Stevanson and co-workers53 reported isomer inversion of trioxalate chromium (III) complex 68 solution in water upon irradiation with right and left circularly polarized light at 546 nm (Scheme 1.15). After irradiating 0.027 M solution of oxalate complex 68 at 1.4 °C in water for 4 h, a photostationary state was achieved. At the photostationary state, ∆A = 9 ´ 10 4; where
∆A = AL-AR is the difference in absorption of solution towards left and right circularly polarized light. When photostationary state was achieved, ∆A remains constant. However, ∆A depended on the temperature, and hence the temperature affected the racemization process. At lower temperatures, ∆A was observed to have higher values. 47
O O O O r-cpl O Cr3+ O O Cr3+ O O O O O O Oxalate = O O O O O 68 68
Scheme 1.15: Optical activation of trioxalate chromium (III) complex 68 in using cpl.
1.9.2.3 Asymmetric fixation
In this type of asymmetric induction by circularly polarized light, one of the isomers is formed predominantly over the other. Kagan and co-workers54 showed the utility of circularly polarized light in the synthesis of hexahelicene by irradiating 1-(b-naphthyl)-2-(3-phenanthryl) ethylene 69 and adding catalytic amount of iodine which eventually resulted in 25% chemical yield of hexahelicene 70 (Scheme 1.16). The product showed an ee of ~ 0.2.
cpl [O] H Benzene,I2 I2 H
69 70
Scheme 1.16: Photochemical asymmetric synthesis of hexahelicene using circularly polarized light.
Although, photochemical asymmetric synthesis with circularly polarized light was successful in some cases, the efficiency was not good enough for synthetic purpose. For example, in asymmetric synthesis by partial decomposition of racemic mixtures method, high 48 optical purity could be expected only at high conversion. This will result in the decomposition of most of the starting material. Most of these reactions with circularly polarized light were designed to decipher the secret of the origin of life on planet earth. As chiral molecules are abundant in the biological systems, the answer on how the first chiral molecule was created on earth should tackle the mystery of life on earth. According to some theories, during prebiotic time, interaction of circularly polarized light with atoms or molecules created chiral molecules, which lead to the origin of life.1,2
For the synthetic community, an organic reaction is considered to be efficient only when it achieves high chemical yield and optical purity (enantiomeric excess/diastereomeric excess).
In order to reach these goals, several strategies were developed for photochemical asymmetric synthesis (Section 1.10).
1.10 Strategies for photochemical asymmetric synthesis
Inbuilt chirality or chiral substituent in the reactant can act as a source of chiral induction.
Even though several strategies were developed in this regard, most of them encountered the challenges of moderate or low optical purity in the photoproduct.
1.10.1 Chiral auxiliary induced diastereoselectivity in [2+2]-photocycloaddition reaction
Tolbert and co-workers55 developed the intermolecular diastereoselective [2+2]- photocycloaddition between trans-stilbene 25 and chiral auxialry containing dialkyl fumarate ester 71 (Scheme 1.17). The cycloadduct formed after photoreaction was subjected to hydrolysis to remove the chiral auxiliary followed by esterification with acidic methanol resulting in the formation of d-truxiante 72 and µ-truxinate 73 (Scheme 1.17, a). Product distribution and the diastereoselectivity depended upon the substituents on fumarate ester. Higher diastereoselectivity 49
(de ~ 90%) was observed with methyl-l-bornyl fumarate ester 71b with nearly exclusive formation of µ-truxinate 73. For di-l-bornyl fumarate ester, the presence of two chiral center led to diastereomers with, moderate yield and low diastereoselectivity in the corresponding products
72 and 73.
This observation was explained based on exciplex formation between stilbene and methyl-l-bornyl ester which favor the formation of µ-truxinate 73 even though the product is sterically hindered compared to d-truxiante 72. However, with di-bornyl ester 71c, formation of exciplex was disfavored with two bulky bornyl group in fumarate ester. This was rationalized based the blue shift of emission from exciplex of dimethyl fumarate 71a and stilbene along with the lower relative quantum yield of product formation compared to that of dimethyl fumarate ester (which has relatively less bulkiness). Dibornyl fumarate ester favor the formation of d- truxiante, which has all trans substitution. This was explained based on 1,4-biradical formation, where the biradical formed in the first step orient itself to a stable confirmation followed by the second bond formation leading to the formation of cyclobutane adduct (Scheme 1.17, b). 50
O 1. h ~ Medium pressure Ph ν Ph CO2CH3 Ph CO2CH3 OR Hg vapor lamp, benzene + 1 + O Ph 2. MeOH, HCl Ph CO2CH3 Ph CO2CH3 OR2
54 55 56 57
55a R1 = R2 = methyl
55b R1 = CH3, R2 = l-bornyl
55c R1 =R2 = l-bornyl
55d R1 = CH3, R2 = (R)-2-methylbutyl
55e R1 = R2 = (R)-2-methylbutyl
(a) (b)
Ph Ph CO2R CO R 2 CO2R RO2C Ph Ph RO2C RO2C
Exciplex formation 1, 4-biradical
Scheme 1.17: Diastereoselective [2+2]-photocycloaddition of stilbene 25 with chiral dialkyl fumarate 71. (a). Exciplex formation. (b). 1,4-biradical formation. 51
Table 1.3: Diastereomeric excess, relative quantum yield and emission maximum for the exciplex formation for the reaction of stilbene with chiral dialkyl fumarate 71a-e.
Product yield (% de) Emission Relative maximum Entry Fumarate quantum µ-truxinate d-truxinate lmax in nm yield (for exciplex) 1 71a 50 (0.0) 2 (0.0) 1.0 520 2 71b 20 (90.4) 5 (20.0) 0.035 505 3 71c -- 10 (20.0) 0.011 500 4 71d 35 (19.5) 5 (0.0) -- -- 5 71e 30 (20.0) 20 (0.0) -- --
Lange and co-workers56,57 reported diastereoselective [2+2]-photocycloaddition of chiral enone 74 with cyclopentene 75 (Scheme 1.18). The reaction resulted in the formation of two diastereomers; cis-anti-cis disteromer 76 and cis-syn-cis diastereomer 77. Enone with chiral auxiliary (-)-8-phenylmenthyl 79a was efficient in inducing diastereoselectivity (79% for 77 vs
30% for 76) over enone with (-)-menthyl group 79b or enone with (-)-bornyl group 79c.
Diastereoselectivity of product 76 showed solvent and temperature effect. In polar protic solvent such as MeOH or MeOH/5% acetic acid, higher diasteroselectivity was observed in 76. This was attributed to the s-trans form of enone being favored in polar solvent than the s-cis form. Enone
74 in its s-trans form has more stereo chemical differentiation over s-cis form, that resulted in higher diastereoselectivity. Lowering the temperature also showed increase in diastereoselectivity in the product. 52
* * R O O H R O O H CO R* 2 hν + +
H H H H O O O
74 75 76 77
cis-anti-cis cis-syn-cis
Me Me MeH R* =
Ph a b c (-)-8-phenylmenthyl (-)-menthyl (-)-bornyl
Chiral auxiliary Product 76 de (%) Product 77 de (%) 74a 30 79 74b 18 25 74c 4 --
Scheme 1.18: Diastereoselective [2+2]-photocycloaddition of enone 74 with cyclopentene 75.
1.10.2 Chiral auxiliary induced diastereoselectivity in [4+2]-photocycloaddition reaction
Okada and Oda’s group reported diasteroselective intramolecular photocycloaddition of anthracene tethered with fumarate ester of l-menthol 78a and l-borneol 78b (Scheme 1.19).58
Asymmetric induction in (9-anthryl)-methyl bornylfumarte 78a was found to be relatively less
(de = 9%) compared to that in (9-anthryl)-menthylfumarte 78b (de = 35%) at room temperature.
At a temperature of -20 °C, de increased to 55%. This reaction proceeded through the singlet state. Also, an efficient quenching of anthracene fluorescence with fumarate tether was observed. 53
O O
RO2C hν O CO2R
O
78 79
R = H R =
a = bornyl b = menthyl
Scheme 1.19: Intramolecular [2+2]-photocycloaddition of 9-anthryl-fumarte ester 78.
1.10.3 Chiral auxiliary induced diastereomer equilibration
Okada and Oda’s group also reported diasteroslective photo-equilibration of (R)-1-(1- naphthylethyl) amide of spirocyclopropane in the presence of sensitizers (Scheme 1.20).59
Irradiation of equimolar mixture of diastereomer 80a and 80b in benzene in the presence of sensitizer resulted in equilibration to form a photostationary state (PSS). Diastereomeric ratio at photostationary state depended on the triplet energy of sensitizer. Sensitizer with lower triplet energy resulted in higher diastereomeric ratio. p-Phenylacetophenone with triplet energy of 61.1 kcal/mol resulted in a diastereomeric ratio of 86:14 for 80a:80b. No diastereoselectivity was observed for photo-equilibration with acetophenone, which has a triplet energy of 73.7 kcal/mol.
Based on the triplet energy of sensitizer, it was proposed that sensitizer transfers energy to naphthyl moiety, which in turn does intramolecular energy transfer to fluorenespirocyclopropane moiety. Product distribution in the photostationary state (80a vs 80b) was explained on the basis of efficiency of intramolecular energy transfer. Efficient energy transfer by an electron exchange mechanism requires efficient overlap of molecular orbitals of reacting species. However, it 54 decreases with steric hindrance between the interacting species. In the structure of 80a such interaction would be disfavored compared to that in 80b due to steric interaction between methyl and fluorine moiety which is reflected in the observed diastereoselectivity.
hν Sensitizer COR
COR
80a 80b H Me N R = (R)-(+)-MeCHNpNH
O H Me N Np H O NH Np Me H
80a 80b
Scheme 1.20: Diastereoselective photo equilibration by sensitization.
1.10.4 Chiral complex induced rearrangement
Nitrones are expected to form complex with hydrogen bond donor such as electron deficient alcohol through its electron rich oxygen. If the complexing agent is chiral in nature, then it can be expected to induce chirality for possible chemical transformation. This would be advantageous over traditional chiral auxiliary induced asymmetric synthesis, where 55 stoichiometric amount of chiral auxiliary is required for the reaction. If complexing agent can induce chirality in the product formation, then technically it can be used in catalytic amount.
Boyd and co-workers60 showed photochemical chiral induction for the conversion of nitrones 81 to oxaziridines 82 in the presence of chiral complexing agent (+)-triflouro-1- phenethyl alcohol, which was used as a solvent (Scheme 1.21). The diastereomeric ratio increases with bulky substituent at the imine nitrogen of nitrone. It also increased with lowering the temperature. Interaction of nitrone with bulky t-butyl group at the imine nitrogen atom and phenyl ring at the imine carbon atom resulted in the formation of oxaziridine with moderate diastereomeric excess of 31%. The authors proposed that nitrone formed complex with (+)- triflouro-1-phenethyl alcohol through hydrogen bonding. C-H hydrogen of triflouro-1-phenethyl alcohol is acidic because of triflouro group which would be stabilized by electron rich phenyl group at the imine carbon. So, electron withdrawing substituent on phenyl ring at imine carbon destabilized the complex. Hence, with those substrates, lower diastereomeric ratio was observed
(de = 0.4% for 81c). 56
X X hν O (+)-CF CH(Ph)OH 3 O N N R1 R1 R2 R2
81 82
O H a R1= H, R2 = t-Bu, X = Ph O R2 N Ph b R1= H, R2 = t-Bu, X = 4-BrPh H CF3 R1 c R1= H, R2 = t-Bu, X = 4-NO2Ph X d R1= Ph, R2 = t-Bu, X = Ph 83
Scheme 1.21: Chiral solvent mediated photochemical asymmetric induction for the conversion of nitrone 81 to oxaziridine 83.
Table 1.4: Diastereoselectivity for photochemical asymmetric induction of nitrones with chiral complexing solvent under various conditions.
Compound Temperature (°C) Yield (%) Optical yield (%) 81a -40 100 11.5 81b -38 95 1.4 81c -40 63 0.4 81d -78 50 31
1.10.5 Photochemical asymmetric induction in crystalline media
Photochemical reaction in crystalline media has been extensively explored by Schmidt and co-workers. Schmidt developed several postulates, which govern the reactivity in solid state called as topochemical postulates. One of the important outcome of this postulate is that reactivity in solid state is governed not only by its intrinsic reactivity, but by the surrounding environment of reactant molecules in the crystal. For dimerization reaction in crystalline media, 57 reacting bond should be at or less than 4.2 Å. This distance is called the Schmidt distance. If the reacting bond is at a distance higher than Schmidt distance then dimerization reaction will not be favored.
Trans-cinnamic acid can crystalize in three forms called a (84a), b (84b), and g(84c).
Among them, a-and b-form has reacting double bond for dimerization within the Schmidt distance (Figure 1.20).61 In a-form the molecules are arranged in a head-tail fashion, whereas in the b-form they are arranged in head-to-head fashion. Dimerization of a-form of cinnamic acid crystals gives head-tail adducts called a-truxilic acid 85a, whereas the dimerization of b-form of the same gives head-to-head adduct called b-truxilic acid 85b (Scheme 1.22). In the g-form, distance between the reacting bonds for dimerization is more than Schmidt distance and hence no dimerization was observed.
Figure 1.19: a and b form of cinnamic acid crystal and the distance of separation of reacting bond.48, 61 (Reproduced from reference 48 with permission from American Chemical Society,
2016). 58
HOOC Ar Ar hν
COOH Ar COOH 84a 85a α - form α - truxilic acid
Ar COOH Ar hν
COOH Ar COOH 84b 85b β - form β - truxilic acid
Ar hν No reaction COOH 84c
γ - form
Scheme 1.22: Dimerization reaction of a, b and g cinnamic acid (84a, 84b, and 84c) in crystalline media.
Chiral induction for photochemical reaction in crystalline media can be achieved if the reacting molecules are crystallized in chiral space group. Out of 230 space groups, 65 space groups are chiral in nature. So, the reacting molecule should be crystallized in one of these 65 space groups. If the reactants are optically pure (i.e. if they have inbuilt chirality), then they crystallize in one of the spaces. Irradiation of chiral crystal result in product with optical purity close to 100%.
If the reactant is a racemic mixture, each enantiomer can be crystallized separately from its solution. Seeding with optically pure isomer results in the crystallization of only one of the isomer, leaving the other isomer intact. The other isomer can be crystallized separately. 59
Even if the reactant is lacking any chiral unit, it can get crystallized spontaneously in a chiral space group through seeding of chiral crystal in a melt. This is called as spontaneous crystallization62 a process pioneered by Sakamoto and co-workers.
Scheffer and co-workers63 demonstrated di-p-methane rearrangement in chiral crystalline media to get rearranged products with very high enantiomeric excess (Scheme 1.24). Diester derivative of dibenzobarrene 85 on crystallization from solution results in two crystalline forms, out of which, one of them is chiral in nature. Irradiation of chiral crystal led to rearranged product 86 with enantiomeric excess of >95%.
RO2C CO2R RO2C CO2R hν
R = CH(CH3)2 85 86
> 95% ee
Scheme 1.23: Chiral induction through crystalline media for di-p-methane rearrangement.
1.10.6 Photochemical asymmetric induction in supramolecular system
Supramolecular systems have collection of molecules which are held together by weak forces (< 5 kcal/mol) such as H-bonding, cation-p, p-p or hydrophobic interactions.48
Supramolecular systems mediated chemical reactions have host-guest type of interactions, where reactant act as a guest and supramolecular system act as a host. Such systems have confined cavity of specific size where a reactant molecule can enter and experience entirely different atmosphere. Thus, typically reactant molecules show different reactivates in the absence and in the presence of supramolecular system (Figure 1.20). Several supramolecular systems such as 60 zeolites, cyclodextrins, molecular templates, clay, micelles, octa acids are employed for photochemical reactions. These systems modified with chiral units are also employed for asymmetric induction in photochemical reactions.
+
Guest molecule Host molecule Gest -host complex
+ Separated host- gest molecule after reaction
Figure 1.20: Host guest interaction in supramolecular photocatalysis.
Zeolites are crystalline aluminosilicates having uniform channels and cavities.
Ramamurthy, Scheffer and co-workers64 reported chiral induction for Norrish type II reaction of cis-4-tert-butylcyclohexyl ketone derivative 87 to corresponding cyclobutanol 88 in zeolite incorporated with (-)-ephedrine with an optical yield of 30% ee (Scheme 1.24, Equation 1). The reaction was carried out in solid phase of ketone, chiral inductor and zeolite complex. The reaction was also performed in a slurry of mixture of reactants in hexane. Both the experiments resulted in identical optical yield. However, in solid phase, reaction occurred with longer 61 irradiation times. At 20°C, maximum value of ee (30%) was obtained for the occupancy number
1.3 (number of chiral inductor per zeolite cage).
COOMe COOMe
O hν HO (1) Zeolite/(-)ephedrine t-Bu Me t-Bu Me 87 88 ee = 30%
Ph O Ph O O O O Ph O hν + (2) Zeolite/Ephedrine H H 89 90a 90b ee = 78%
H O Ph H O Ph hν N N (3) N Ph Zeolite/Norphedrine + O H O O H ee = 50% 91 92a 92b
Scheme 1.24: Chiral induction in zeolites media for Norrish type II reaction of 87, photocyclization of 89 and 91.
Ramamurthy and co-workers also demonstrated chiral induction in the photocyclization of tropolone ethyl phenyl ether 89 and 1-(3-phenyl propyl)2-pyridone 91 in the presence of modified zeolite65 to get an enantiomeric excess of ee = 78% and ee = 50% respectively in the corresponding photoproducts (Scheme 1.24). Epherine was used as the chiral inductor. 62
Cyclodextrins (CD) are cyclic oligosaccharides consisting of glucopyranose unit. CDs with 6,7 and 8 glucopyranose units are called a, b and g cyclodextrins respectively. The structure of cyclodextrin consists of a cavity which can be occupied by a guest molecule of suitable size.
Depending on the size of cavity and the size of guest molecule it can have either one or more than one guest molecules at a time. Chiral environment in the cavity due to glucopyranose unit can be utilized to induce chirality on guest molecule undergoing reaction in the cavity.
Turro and co-workers demonstrated chiral induction in b-cyclodextrin for the formation of R-(-)-benzoin 94 from benzaldehyde 93 under photochemical condition.66 Reaction involved triplet state of aldehyde 93 (Scheme 1.25) which abstracted hydrogen from ground state aldehyde followed by coupling resulting in the formation of benzoin 94. When a-cyclodextrin was employed, no reaction was observed. With g-cyclodextrin, along with benzoin product 94, 4- benzoyl benzaldehyde 95 was also formed. Formation of 95 was due to larger cavity size of g- cyclodextrin that facilitated benzoyl radical to move around and abstract the hydrogen at the para position of benzaldehyde. 63
O H O H hν H O HO
93
O OH H + H 95 O O 94 Formed only with γ-cyclodextrin R-(-)-benzoin (formed with α-cyclodextrin) % ee = 15%
= α or γ-cyclodextrin
Scheme 1.25: Cyclodextrin mediated chiral induction in benzoin 94 formation from benzaldehyde 93.
Bach and co-workers67 reported chiral template mediated enantioselective intramolecular
[2+2]-photocycloaddition of coumarin derivative with alkenyl tether 96 (Scheme 1.26). Chiral template (+)-98 derived from Kemps acid was synthesized, that formed hydrogen bonds with coumarin derivative 96 in enantio-face selective fashion. This chiral face bias held in inducing enantioselectivity during the reaction to achieve 88% ee at -15 °C in toluene. 64
H O hν Toluene, (+)-98 O H N O N O H H 96 97 ee = 88%
O
N O H H N O N H O O N O N
98 1:1 complex of 96 and 98
Scheme 1.26: Chiral template mediated photocycloaddition of coumarin derivative 96.
1.11 Atropselective photoreactions - Photochemical asymmetric induction through axially
chiral chromophore.
Even though there are several strategies for asymmetric photochemical transformations as described in the previous section, most of them required special condition and are not very efficient under ambient condition. Strategies such as circularly polarized light induced photochemical transformation has a challenge of obtaining a reasonable optical purity of photoproduct. In spite of excellent asymmetric induction in chiral crystalline media, for this method to be applicable, the reactants must be crystalline in nature, which is not the case for most of organic compounds. Most of the previously reported photochemical asymmetric synthesis were lacking a general strategy which can be applied for most of the system. In those lines Sivaguru and co-workers68 developed a method called “axial chirality to point chiral 65 transfer strategy” where, axial chirality of reactant molecule was utilized to induce point chirality in the photoproduct.
Axially chiral molecules are called as atropisomers,69 which exhibits chirality due to restricted bond rotation. The isomers are designated with notation P (for positive helix) and M
(for minus helix) following Cahn-Ingold-Prelong rules.70
A A D
D C C B B
P - form A > B > C >D
Decreasing priority
A A C C D
D B B
M - form
Figure 1.21: Schematic view of atropisomeric molecules and its designation a P and M isomers.
Biaryl molecules such as biphenyls, binaphthyls exhibit atropisomerism and are extensively used as chiral inductors in thermal reactions.70,71 Yamamoto and coworkers used 66 aluminium binaphthyl complex 102 in hetero Diels-Alder reaction of butadiene derivative 99 with benzaldehyde 93 leading to cis adduct 100 with 95% ee (Scheme 1.27).72
OMe Me Me Me 1) PhCHO - 93 O O cat. 102-(R), 0 °C + O Ph O Ph Me SiO 2) CF COOH 3 3 Me Me Me
99 100 101 ee = 95%
SiPh3
O Al Me O
SiPh3 102
Scheme 1.27: Atropisomeric binaphthyl derived catalyst 102 in asymmetric Diels-Alder reaction of benzaldehyde 93 and 1,4-butadiene derivative 99.
Axial to point chiral transfer strategy for photochemical reaction was developed based on
Havinga’s non-equilibrating excited rotamer (NEER) principle73,74 and Curan’s prochiral auxiliary approach for asymmetric synthesis.75,76
Curran and coworker proposed the concept of ‘prochiral auxiliary’ for asymmetric synthesis. 76 In this strategy, a substrate and prochiral auxiliary are combined in the presence of chiral catalyst to form a substrate-chiral auxiliary bound system, which after reaction can be detached from the product there by regenerating the prochiral auxiliary (Figure 1.22). 67
Prochiral Chiral Chiral Substrate catalyst Substrate + auxiliary auxiliary
Δ Chemical transformation
Prochiral Chiral Product Detach Product + auxiliary auxiliary
Figure 1.22: Curan’s prochiral auxiliary model for asymmetric synthesis in thermal reaction.
Earlier nonbiaryl atropisomeric systems developed by Curran and co-workers involve acryl anilides derivative for atropselective thermal transformation. Atropisomeric ortho-iodo-N- methyl acrylanilde 103 (97% ee) underwent cyclization in the presence of tributyltinhydride
(Scheme 1.28) to cyclized product 104 with 87% ee. Racemization barrier of acrylanilide was high enough to prevent racemization during the course of reaction resulting in efficient transfer of axial chirality.
O O CH O CH 3 CH3 3 N N N
I Bu3SnH
Et3B/O2 25 °C, C6H6
103 104 M-97% ee R-87% ee
Scheme 1.28: Intramolecular atropselective radical cyclization of acryl anilide 103.
However, under photochemical reaction conditions, energetics of reactant molecules will be very high compared to thermal condition. Therefore, racemization in the excited state should be taken into consideration. In this case, non-equilibrating excited rotamer (NEER) principle could be utilized for a proper design of reacting chromophore to deal with this challenge. 68
According to Havinga’s NEER principle,73,74 “conjugated diene which are in equilibrium in the ground state will be not be in equilibrium in the excited state.”
This principle can be visualized with isomerization of 1,4-butadiene 1 under photochemical condition (Figure 1.23). In the ground state, both the rotamer s-cis and s-trans are in equilibrium because of the free rotation around C2 - C3 single bond. However, in the excited state, because of the diradical nature, C2 - C3 bond will have partial double bond character and the rotamer equilibration will be restricted in the excited state. By designing molecules with high racemization barrier around a pivotal bond, the reactivity of rotamers can be controlled in the excited state based on NEER principle.73,74
A* B*
hν * hν hν
Energy Energy 1-s-cis 1-s-trans P1 A ΔG B P2 Non- equilibrating excited rotamer
Figure 1.23: A schematic diagram for NEER principle.
1.11.1 Atropselective photoreactions68
Sivaguru and co-workers77 demonstrated the axial chirality to point chiral transfer strategy for 6p-photocyclization atropisomeric acryl anilides 105 (Scheme 1.28). The bulky t- butyl group at the ortho position in 105 led to restricted C-N aryl bond rotation. Chiral induction happened in the first step of photocyclization between the carbon atom bearing t-butyl group (C2 position) and the carbon atom bearing R1 group followed by the elimination of t-butyl group as
2-butene. Second step involved proton migration resulting in the mixture of cis and trans diastereomers (106 and 107 respectively). Various solvents (MeOH, acetone, CHCl3, 2:1 mixture 69
of C6H6/THF) were screened under irradiation of 450 W medium pressure mercury vapor lamp.
High enantiomeric excess in both cis and trans isomer were observed.
R1 R1 2 hν 2 R2 2 R2 solvent N + 6 0 - 3 °C 1 3 R3 N R3 N O O R R 6 6 R2 105 106 107 (cis) (trans) ee = 85 - 99 % ee = 87 - 99 %
a R1 = R2 = CH ; R3 = H 3 Solvent = Acetone, CHCl , MeOH, CH 3 2 C6H6/THF (2:1) 3 b R1 R2 = ; R = H CH2
1 2 3 c R = H; R = CH3; R = H
1 2 3 d R = CH3; R = CH3; R = t-Bu
CH2 e R1 R2 = ; R3 = t-Bu CH2
Scheme 1.29: 6p - Photocyclization of atropisomeric acrylanilides 105.
Atropselective photo transformation was also achieved for 4p-ring closure of 2- pyridones 108 (Scheme 1.30).78 Ortho substituent on the phenyl ring imparted atropisomerism in the system. Temperature effect on chiral induction (atropselectivity) was studied with various solvents (toluene, acetonitrile, MeOH, H2O) at different temperatures. Eyring plot revealed that, for substrate 108a featured a t-butyl substituent, steric effect (entropic factor) had a major contribution in diastereomeric transition state. However, for 108b and 108c that can form intra- and inter rmolecular hydrogen bonds with polar solvents featured both enthalpic and entropic 70 contributions to the difference in diastereomeric transition state energy that was reflected in the temperature dependence of atropselectivity.
H H O R2 N O hν R2 N R1 Solvent R1 R1 Temp. R1
108 109
ee = 22 - 97 % 1 2 a R = R = CH3 Solvent = Toluene, 1 2 acetonitrile, MeOH, H2O b R = CH3; R = OH
1 2 c R = Ph; R = OH
Scheme 1.30: 4p - ring closure of atropisomeric 2-pyridones 108.
Effect of atropisomerism was also evaluated for diastereoselective photoreactions. Photo irradiation of atropisomeric acryl imides 110 resulted in both cross 111 and straight 112 [2+2]- photocycloaddition with cross addition product formed in major amount (Scheme 1.31).79
Presence of bulky t-butyl group imparted atropisomerism in the acrylimides resulting in high atropselectivity. Acrylimide with two bulky groups in the phenyl ring 110a and 110b resulted in diasteroselctivity of 99:1 for cross vs straight addition product, whereas substrate 110c which was lacking t-butyl group showed only 82:18 diasteroselctivity. Reaction was performed under both direct and sensitized irradiation and similar results were observed under both the conditions. 71
h ν O O 2 O R2 Direct/sensitizer, R2 R Solution/Solid state N N N rt. Ph O R1 1 1 Ph O R Ph O R 110 111 112 dr = 82 - 99% a R1 = tBu; R2 = H Solvent = Acetonitrile, MeOH, acetone b R1 = tBu; R2 = tBu
Sensitizer = Acetone, thioxanthone, c 1 2 R = H; R = H Xanthone, benzophenone
Scheme 1.31: Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric acrylimides 110.
Diastereoselectivity and stereoselectivity was explored for [2+2]-photocycloaddition of atropisomeric 3,4-dihydro-2-pyridones 113 (Scheme 1.32).80 Reaction proceeded by both triplet sensitization and direct irradiation. Stability of biradical formed due to the allylic substituent on the phenyl ring was crucial for the observed diastereoselectivity. Substrate 113b generated relatively stable tertiary biradical with longer life time than radical intermediate possible for
113a and 113c.This led with the formation of both diastereomer in the corresponding product
114 and 115. In the case of 113a and 113c, only stable diastereomer was observed which resulted in high diastereoselectivity of photoproduct. 72
H H 1 1 hν R R 1 H 1 H Aceton or R R 1 2 2 R N O solvent/sensitizer R N O R N O R1 Temp. R2
X X X
113 114 115
1 2 ee > 98 % a R = R = X= H dr = 75 - 99 % 1 2 b R = CH3; R = X= H Solvent = Acetone,MeOH
1 2 c R = H; R = X= CH3 Sensitizer = Acetone, xanthone, thioxanthone, acetophenone .
Scheme 1.32: Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric
3,4-dihydro-2-pyridones 113.
Atropisomeric maleimides 116 with alkenyl tether were explored for intramolecular
[2+2]-photocycloaddition (Scheme 1.33).81 Axial to point chirality transfer was very efficient as very high atropselectivity (> 98%) was observed during the phototransformation. The reaction was also diasteroselective with straight addition product 117 observed as the major product and cross addition product 118 as minor product. Reaction proceeded under both triplet sensitization and direct irradiation. Substituents in the maleimide moiety influenced diasteroselectivity by stabilizing 1,4 biradical intermediate formed during course of reaction. 73
3 2 R R 1 1 2 1 R R4 R R3R R R3 2 R4 O O hν R R N O N O O N O 4 Aceton or solvent/sensitizer + X X X Temp.
116 117 118
exo/stright addition endo/cross addition R1 = Me, Ph, Br, Immidazole major product minor product
R2 - R4 = H, Me ee > 98 % dr = 62 - 99 % X = CH2, O, O2SiPh2 Solvent = Acetone,MeOH, ethyl acetate, THF, chloroform, benzene,MCH
Sensitizer = Acetone, xanthone, thioxanthone, acetophenone
Scheme 1.33: Diastereoselective and atropselective [2+2]-photocycloaddition of atropisomeric maleimides 116.
Apart from successful demonstration of atropisomeric molecule for various asymmetric photochemical transformations by Sivaguru and co-workers demonstrated the use of atropisomeric thio urea for organophotocatalysis (Scheme 1.34).82 Thiourea based binaphthyl catalyst 121was employed for intramolecular asymmetric [2+2]-photocycloaddition of coumarin derivatives tethered with alkenyl group 119. The intramolecular [2+2]-photocycloaddition product 120 was formed with high enantiomeric excess of 77-96%. Catalytic cycle involved excited state of catalyst that formed hydrogen bonding through N-H group of thiourea moiety and oxygen centers. The comarin substrate (Figure 1.24). Atropisomeric nature of catalyst provided enantiotopic face differentiation through hydrogen bonding with substrate that induced 74 chirality in the photoproduct with quantitative yield. Successful [2+2]-photocycloaddition of
100% was achieved with enantiomeric excess ranging from 77-96% ee in 120. To decipher the mechanism of reaction, substrate scope was varied with electron donating/electron withdrawing group on reactant coumarin and on binaphthyl catalyst. Electron withdrawing group on catalyst increased the hydrogen bonding ability and hence complexation of substrate resulting in increased efficiency of photocatalysis with high enantiomeric excess in the product.
Photophysical studies showed that at high catalyst loading, the catalyst absorbed light and substrate quenched the excited state of catalyst through exciplex mechanism. But at low catalyst loading substrate catalyst complex was formed that absorbed light resulting in efficient enantioselective reaction.
CF3 F C 3 S
N N CF3 H H OH O
F3C O
Figure 1.24: Substrate catalyst complex with substrate 119a and catalyst 121e. 75
H hν A A 10 mol% 103 H 1:1 (v/v) B O O toluene/m-xylene B O O -78 °C, t (h) 119 120
ee = 77 - 96% 119a A = B = H
119b A = CH3; B = H E X 119c Ar A = F; B= H N N H H 119d F A = OMe; B = H C 119e A = H; B = Me F F D CF3 CF3 F 121 119f A = H; B = Me Ar-1 Ar-2
121a C = OH; D = H; E = H; X = S; Ar = Ar-1
121b C = OH; D = H; E = H; X = O; Ar = Ar-1
121c C = OH; D = H; E = H; X = S; Ar = Ar-2
121d C = OMe; D = H; E = H; X = S; Ar = Ar-1
121e C = OH; D = CF3; E = CF3; X = S; Ar = Ar-1
121f C = OH; D= CF3; E = CF3; X = S; Ar = Ar-2
Scheme 1.34: Organophotocatalysis with thiourea based hydrogen bonding catalyst 121 for intramolecular [2+2] photocycloaddition in coumarin derivatives 119. 76
1.12 Summary
Photochemical reactions provides access to complex strained molecular architectures that are difficult to attain by thermal methods. The nature of excited state dictates the reactivity in a photochemical reaction. Controlling the reactivity in a photochemical reactions has been quite challenging due to the intricate nature dynamics and lifetime of the excited state (s). Irrespective of various strategies developed in the past for asymmetric photochemical reactions, general approach for efficient chiral induction is lacking. In atropselective phototransformations developed by Sivaguru and co-workers, where axially chiral molecules used for inducing point chirality continues to show promise for efficient chiral induction. Following chapter in the thesis describes some approach to manipulate the excited state of carbonyl, alkene and imine chromophores to decipher new reactivity from the excited state(s). Efficiency of axial to point chiral transfer strategy of these new reactivity was also explored.
1.13 References
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86
2 CHAPTER 2: TRANSPOSED PATERNÒ-BÜCHI REACTION
Introduction
In general, photochemical reactions are quite interesting as they can give access to chemical transformations that are relatively difficult and /or not feasible in conventional thermal reactions.
Manipulating the excited state of reacting chromophore often opens up new avenues of reaction and increase the scope of photochemical reactions. In this regard, we thought to engineer the excited state features in a typical Paternò-Büchi reaction.
A typical Paternò-Büchi reaction (Scheme 2.1) involve [2+2]-photocycloaddition of alkene double bond with excited carbonyl group to form oxetane (four membered ring with oxygen).1
The reaction was discovered over more than a century ago by Paternò (1909)2 who irradiated the solution of a carbonyl compound with alkene under sunlight for several days to discover the formation of some new photoproduct. But product characterization was performed by Büchi
(1954)3 who established the structure of photoproduct.
The Paternò-Büchi reaction has been one of the important reaction embraced by the synthetic community as the oxetane skeleton with strained four membered ring (strain energy ~ 110 kJ/mol4) is present in several natural products/lifesaving drugs (Chart 2.1).5,6
Material in this chapter was co-authored by Elango Kumarasamy (EK), Ramya Raghunathan (RR), Sunil Kumar Kandappa (SK), A. Sreenithya (AS), Steffen Jockusch (SJ), Raghavan B Sunoj (RS) and J. Sivaguru (JS).23 EK, RR and SK in consultation with JS synthesized compounds for the study. SJ in consultation with JS carried out the photophysical experiments. AS in consultation with RS performed computational studies. 87
O O
Ph Ph 122a TBR - 93a O + hν Ph H O O 93 121 Ph Ph 122b TBR - 93b
Scheme 2.1: Paternò-Büchi reaction of benzaldehyde 93 with alkene 121. (TBR = Triplet biradical).
AcO OAc OAc NH2 NH2 N N OO N CO2H N H O O AcO OAc OH OH O OH BzO OAc
OH 123 124 125 126 Oxetanocin A Pacitaxol A Oxetin Dicytoxetane HIV inhibitor HIV inhibitor Antibacterial Polycyclic diterpenoid
NH O O H H2N NH2 CO2H O O OH C5H11 O O O O O OH MeO2C Me O OH
127 129 128 130 Maoyecrystal I Miterphorone A Thromboxane A2 Bradyoxetin Anti-cancer High cytotoxicity Promotesplatelet Gene regulation aggregation in soyabean
Chart 2.1: Oxetane ring containing natural products/drugs.5,6
88
2.1 An overview of Paternò-Büchi reaction
2.1.1 A generalized mechanism of a normal Paterò-Büchi reaction11,7
Generally, Paternò-Büchi reaction involves an np* excited state localized on carbonyl group (e.g. 93) reacting with an alkene (e.g. 121) (Scheme 2.1and Figure 2.1). Typically, singlet excited state formed after np* excitation of carbonyl functionality undergoes intersystem crossing to form the triplet np* excited state that reacts with alkene in the ground state to form triplet 1,4-biradical (eg. TBR-93a and TBR-93b). This will be followed by the intersystem crossing to form a singlet 1,4-biradical and then to oxetane photoproduct (122a and 122b) or it can revert to starting material (Figure 2.1). If the singlet excited state of carbonyl group can live longer, it can also form singlet 1,4-biradical with alkene which can form the final product. The likely pathway taken in a typical Paternò-Büchi reaction is depicted in Figure 2.1.
O 1 * 1 49 * O hν O O 51b
1 O + 2 D 2 49
ISC ISC ISC O 3 * 3 * O O 51b ISC O 3D + 2 49 1 3 D - Singlet diradical D - Triplet diradical
Figure 2.1: Mechanism of a normal Paternò-Büchi reaction with an np* excited carbonyl compound. 89
Typically, the np* excited state of carbonyl group involves transition of non-bonding electron from oxygen center to p* orbital which results in an electrophilic nature at oxygen center (Figure 2.2a). But singly occupied p* molecular orbital on the carbon atom will have nucleophilic character. So, carbonyl group in its np* excited state is amphoteric in nature. With electron rich spices it can act as an electrophile through the interaction of ‘n’ orbital from oxygen and p molecular orbital of alkene along the molecular plane. But with electron deficient alkene it acts as a nucleophile through the interaction of p* molecular orbital of carbonyl group with p molecular orbital of electron deficient alkene with perpendicular approach to the alkene double bond.
We questioned our self, if the alkene pp* excited state could be made to react with a ground state carbonyl compound? This will necessitate a perpendicular approach of the ground state carbonyl to the pp*excited state with respect to the plane of the alkene double bond. Such a change in orbital approach could be labeled as “Transposed Paternò-Büchi reaction.
90
(a) (b)
C O
C O C
C
C C np* excited carbonyl group adding to alkene double bond
pp* excited alkene double bond adding to carbonyl group
Figure 2.2: (a) Interaction of np* excited state of carbonyl group with ground state alkene molecular orbital. (b) Interaction of pp* excited state of alkene chromophore with ground state carbonyl group.1,8,9
Nishida and co-workers demonstrated formation of 1,4-biradical in a Paternò-Büchi reaction by the photoreaction of benzophenone 21 with cyclopropyl ethylene derivative 131
(Scheme 2.2).10 The np* excited state of benzophenone adds to cyclopropyl alkenyl derivative to form oxetane product 132 and rearranged product 2,3,4,7-tetrahydrooxepine derivative 133.
Formation 133 occurs through allyl carbinyl intermediate (Scheme 2.2) confirmed the presence of 1,4-biradical intermediate that cyclizes to oxepine product 133. At room temperature oxetane derivative was the major product. But at higher temperature (~130 °C) oxepine derivative 133 was the major product as the cyclopropane ring opening was favored. 91
O Ph O h O + ν Ph Ph Ph Benzene Ph Ph
21 131 Cyclopropyl 132 carbinyl biradical
O O Ph Ph Ph Ph
Allyl 133 carbinyl biradical
Scheme 2.2: Paternò-Büchi reaction of benzophenone 21 with cyclopropyl ethylene derivative
131.
If the pp* excited state energy of carbonyl group is lower than its np* excited state,
Paternò-Büchi reaction can initiate from pp* excited state. Rivas and coworkers demonstrated
Paternò-Büchi reaction of acetylselanophene 134 with alkene 135 through pp* excited state of carbonyl group (Scheme 2.3) to form oxetane derivative 136.11 The reaction also results in
[2+2]-photocycloaddition between C=C double bond of acetylsalenophene and alkene double bond resulting in the formation of cyclobutane derivative 137.
92
O O hν O Se + Se MeOH Se
134 135 136 (22%) 137 (32%)
Scheme 2.3: Paternò-Büchi reaction from pp* excited state of carbonyl group of 134 with alkene
135.
Paternò-Büchi reaction can also be performed through photoinduced electron transfer from excited carbonyl to alkene through a charge transfer state (CT) to form a radical ion pair
(RI) (Scheme 2.4). Radical ion pair can form oxetane product through a 1,4-biradical, or by direct transformation. Feasibility of electron transfer can be predicted from Rehm-Weller equation.12 The radical pair thus formed can be solvent separated that eventually recombines to form the oxetane product or undergo back electron transfer to form the starting material.
93
O
51b
ISC
3 3 3 * * * PET 3 O 49 O O O
CT RI 2 3D ISC BET
O +
3 * 2 49 O
solvent separated radical ion pair
Scheme 2.4: Mechanism of a traditional Paternò-Büchi reaction involving photoinduced electron transfer.
2.1.2 Site selectivity in Paterò-Büchi reaction
In a Paternò-Büchi reaction, if alkene moiety has multiple double one will envision chemoselectivity issues that arise due to the reactivity of one double bond over the other. This is also called as site specificity. The reactivity of double bond depends upon relative nucleophilicity for the attack towards electrophilic oxygen of carbonyl group from its np*excited state. For example, the Paternò-Büchi reaction of benzophenone 93 and 2-methylfuran 138 exclusive addition happens to the more substituted double bond (Scheme 2.6).13 On the other hand with benzaldehyde 93 addition happens to both the double bond with less selectivity (45:55 for 139a:139b) as shown in Scheme 2.5. This difference in site selectivity was explained based on difference in triplet energy of benzaldehyde 93 and benzophenone 21. Excited benzaldehyde 94 being more energetic because of its higher triplet state energy (~ 71 kcal/mol) vs that of benzophenone (~ 69 kcal/mol) results observed reactivity and/or selectivity.
H CH3 O hν O O O O toluene O + + Ph Ph H Ph H H H H 93 138 139a 139b 139a : 139b = 45 : 55
Scheme 2.5: Site selective Paternò-Büchi reaction of benzaldehyde 93 with 2-methl furan 138.
hν O O O toluene O + Ph Ph Ph Ph 21 138 139c
(exclussive product)
Scheme 2.6: Site selective Paternò-Büchi reaction of benzophenone 21 with 2-methyl furan 138.
2.1.3 Regioselectivity in Paterò-Büchi reaction
Regioselectivity in Paternò-Büchi reaction depends on the relative nucleophilicity of alkene carbons. Carless and co-workers demonstrated regiospecific Paternò-Büchi reaction between benzophenone 21 and uracil derivative 140 (Scheme 2.7). 13,14 Electron deficient oxygen attacks carbon bearing methyl group with higher selectivity.
O O O R1 R1 Ph O R1 hν Ph Acetonitrile N O N + N + Ph Ph Ph O 2 O N O N O N R R2 Ph R2
21 140 141 142
a: R1 = Me, R2 = H 141a : 142a = 71 : 29
1 2 141b : 142b = 19 : 81 b: R = H, R = Me 95
Scheme 2.7: Regioselective Paternò-Büchi reaction of benzophenone 21 and uracil derivative
140.
2.1.4 Stereoselectivity in Paterò-Büchi reaction8,15,16
In a Paternò-Büchi reaction originating from a np* triplet excited state, stereochemistry of photoproduct depends upon the configuration of 1,4-biradical formed after intersystem crossing. Intersystem crossing occurs with a configuration where singly occupied orbital of 1,4 - biradical are perpendicular to each other. Typically, this major product formed will be the one which possess stable configuration of 1,4-biradical or the diradical that undergoes facile intersystem crossing. In the schematic representation of 1,4-biradical with configuration (a) in
Scheme 2.8, where singly occupied orbitals are orthogonal is preferred to form the product. This model for rationalizing the reactivity of Paternò-Büchi 1,4-biradical is called as Griesbeck model.14, 15
1 O R O H
H R1 R2 H R2 H (a) (b)
O O
R2 R1 R2 R1
Major product Minor product Scheme 2.8: Griesbeck model of 1,4-biradical in Paternò-Büchi reaction.
Bach and co-workers demonstrated diastereoselective Paternò-Büchi reaction of cyclic amide 143 with aldehyde functionalized Kemp triacid derived chiral auxiliary 144 (Scheme
2.9).18 The reaction involves formation of exciplex through hydrogen bonding between the 96
substrate and chiral auxiliary to get high diastereoselectivity of 89:11. When R = CH3, hydrogen bonding was disfavored resulting in racemic mixture in the photoproduct.
O O O
H N N O H O H hν Benzene + O O + O NR NR NR O N O O O O O O H
143 144 145 146
a: R = H 145a : 146a = 89 : 11 b: R = CH 3 145b : 146b = 50 : 50
Scheme 2.9: Diastereoselective Paternò-Büchi reaction controlled through Kemp’s triacid derived chiral auxiliary.
2.2 Transposed Paterò-Büchi reaction
Usually in a normal Paternò-Büchi reaction as described in the literature that typically involves np* or pp* excited state localized on carbonyl group. But one can also visualize the formation of Paternò-Büchi type of product through pp* excited state of alkene reacting with a ground state carbonyl partner. As the reactive orbitals are transposed, the reaction could be termed as “Transposed Paternò-Büchi reaction” (Scheme 2.10).
* O hν O + Normal Paternò-Büchi reaction 1 2 R1 R R2 R2 R1 R R1 R2 Excited ketone
* O hν O + Transposed Paternò-Büchi reaction 1 1 1 2 R R 2 2 R R R R 1 2 Excited R R alkene
Scheme 2.10: Normal vs transposed Paternò-Büchi reaction. 97
Even though both normal and transposed Paternò-Büchi reaction involve similar type of product formation (i.e. oxetane), the trajectories of approach of reacting orbitals are different. In the case of normal Paternò-Büchi reaction, non-bonding n orbital at oxygen center is oriented along the plane of the C-O bond and p orbital is perpendicular to the molecular plane (Figure
2.2b). For an pp* excited carbonyl group reacting with a ground state alkene the approach isalong the molecular plane (Figure 2.21). On the other hand, a perpendicular approachwill be favored with the excited alkene reacts with a ground state carbonyl partner. This scenario is built on
Duben-Salem-Turro rule.9,19
As the orbital in these two types of reactions can have entirely different outcome in the stereochemistry of photoproduct, Sivaguru and co-workers demonstrated efficient axial chirality to point chiral transfer strategy for intramolecular [2+2]-photocycloaddition of atropisomeric six membered enamide tethered with alkenyl chain 102 (Chapter 1, Scheme 1.31).20 Driven by the curiosity we developed the strategy for intramolecular [2+2]-photocycloaddition involving enamide with an aldehyde or ketone functionality. Depending on the nature of irradiation (direct vs sensitization) and the nature of ketone group (i.e. methyl ketone or phenyl ketone) normal vs transposed Paternò-Büchi reaction can be envisioned in such a system (Scheme 2.11). 98
O O N Excited carbonyl * group reacting with R1 a ground state hν alkene Excited carbonyl R1 = Ph Normal Paternò- O Büchi reaction O O O N N R1 R1
Transposed Paternò- hν Büchi reaction Excited alkene * reacting with a O ground state O N carbonyl group
R1
Excited alkene 1 R = Me, H
Scheme 2.11: Normal vs transposed Paternò-Büchi reaction of five membered enamide chromophore tethered with alkyl/aryl ketone. 99
2.3 Evaluation of enamides for Transposed vs Normal Paterò-Büchi reaction
Boc Boc NH2 HN HN NH2 NH2 O-t-Bu OH
O OTIPS
147 148 149 150 151
O O O N O N O N N OH O
O O O OTIPS OTIPS
152 153 154 155 156a
O N O N O O O O N O N N O
Ph
156b 156c 156d 156e 156f
O O O O O O O N Ph N N N N O
156g 157a 157b 157c 158
O O O
Ph O S
159 20 22
Chart 2.2: Structure of enamides, its photoproduct and compounds used for its synthesis.
100
To evaluate normal vs transposed Paternò-Büchi reaction, substrates 156a (aldehyde),
156b (phenyl ketone derivative) and 156c (methyl ketone derivative) were synthesized by employing the strategy as shown in scheme 2.12. Synthesis of phenyl ketone 156b and methyl ketone 156c are reported elsewhere.21 For the synthesis of aldehyde 156a synthetic Scheme 2.12 was followed.
tert-Butylcarbonyl (Boc) protection of commercially available 2,4,6-trimethyl aniline 147 resulted in the formation of N-Boc aniline derivative 148. It was then subjected to ortho- metalation with sec-butyl lithium followed by the addition to of Boc anhydride resulting in the formation of carbamate 149. Lithium aluminium hydride reduction of 149 and Boc deprotection using boiling water resulted in the formation of aminol 150. The alcohol group of 150 was protected with TIPS group (triisopropyl silyl group) by reacting with TIPSCl utilizing imidazole to access 151. Reaction of 151 with 2,2-dimethyl succinic anhydride 152 to get the imide 153.
The DIBAL-H reduction of imide 153 followed by elimination and TIPS deprotection resulted in the formation of enamide alcohol 155. Oxidation of 155 in the presence of Dess-Martin periodinane in dichloromethane solution resulted in the formation of aldehyde 156a (Scheme
2.12). 101
Boc Boc NH HN HN 2 sec-BuLi, -45 oC, THF, 15 min. O-t-Bu (Boc)2, THF 1. LiAlH4, THF, rt, 2 h (Boc) O, 5 min. O reflux, 4 h 2 2. H2O, Reflux, 6 h 95% 95% 85% 147 148 149
1.Anhy. Toluene O O NH2 NH2 45 °C, 2 h N OH TIPSCl, DMF 2.AcOH, AcONa. 70 oC, 2 h Reflux, 2 h OTIPS OTIPS O O 95% O 70%
150 151 152 153
1. DIBAL, DCM, N O TBAF, THF, N O DMP, DCM, N O -78 °C, 30 min reflux, 2 h rt, 2 h OH O 2. MsCl, Et3N, DCM, 0 oC, 2 h OTIPS 75% 92%
75% 154 155 156a
Scheme 2.12: General scheme for the synthesis of aldehyde 156a.
Photoreactions of enamide 156 were performed using 450 W medium pressure mercury vapor lamp as the source of irradiation (Table 2.1). Reaction was performed under direct irradiation (without any sensitizer) as well as in the presence of sensitizer. For direct irradiation condition THF was employed as the solvent for the reaction. For xanthone sensitizer, acetonitrile was used as solvent. When reaction was carried out in acetone, it acted both as solvent and sensitizer.
With atropisomeric substrates, 156a and 156b, reaction was performed with racemic mixture of P and M isomer as well as with pure atropisomer (either pure P or pure M form).
Separation of atropisomer was achieved by using HPLC on a chiral stationary phase.
Substrate 156a that features an aldehyde tether and enamide C=C double bond underwent efficient Paternò-Büchi reaction at room temperature in acetonitrile in the presence of 30 mol% 102
of xanthone sensitizer (ET = 74 kcal/mol) to form oxetane product 157a in 52% isolated yield.
Similar condition was employed for the photoreaction of phenyl ketone 156b, at -30 °C to isolate 62% of oxetane product 157b. When acetone was used as solvent and sensitizer, yield was improved to 92% for 157b. The reaction was also efficient in the absence of sensitizer.
Irradiation of 156b in THF (i.e. no sensitizer) resulted in the formation of 157b with 62% of isolated yield. However, for the methyl ketone substrate 156c, reaction was successful only in the presence of sensitizer (acetone). In the absence of sensitizer (i.e. in THF), there was no reaction as only 7% of conversion was observed even after direct irradiation for 2.5 h.
Conversion was calculated by analyzing the reaction mixture with 1H NMR spectroscopy in the presence of triphenyl methane as internal standard. Following equation was employed for calculating the conversion.
�������� �� ������� � ��� = ��� × × Equation 2.1 �������� �� �������� �
Where molA= molarity of analyte, molI = molarity of internal standard, NA and NI are number of nuclei corresponding to the integration of analyte and standard respectively.
103
Table 2.1: Transposed vs normal Paternò-Büchi reaction of enamide substrate. a
O O N O h ν 1 N 2 solvent/sensitizer R O R R2 rt, t (h), N R1 2
2 1 R R = H, CH3, Ph 2 2 R R = H, CH3, 156a-c 157a-c
Entry Substrate Solv/sens. t (h) product Yield [%], [%] ee
O O O N O N 1 MeCN/Xanthone 0.5 Yield = 52%
156a 157a (A)-156a (B)-157a 72% eeb (B)-156a (A)-157a 88% eeb
O O c,d O Acetone 8 94 (82) N Ph N 2 O THF 3 Yield = 75%e Ph MeCN/xanthone 12 62d,e
156b 157b
(+)-156b (-)-157b 89% eed (-)-156b (+)-157b 88% eed
O O N O N f O acetone 2.5 Yield = 73% 3 MeCN < 7.0c
156c 157c aPhotoreactions were performed at room temperature using 450 W medium pressure mercury lamp. Acetone as solvent and sensitizer or MeCN/30mol % sensitizer. (+) and (−) represent the sign of optical rotation (MeOH at 25 C). A and B refer to the elution order for a given pair of enantiomers in the HPLC. Reported values are an average of 3 runs with ±3% error. The yields reported are isolated yield after column chromatography. The numbering positions are labeled as a guide to denote stereochemistry. The ee values were determined by HPLC on a chiral stationary phase. bThe optical purity of PkA and PkB of 157 are 76 and 92%, respectively. cConversion (%Convn.) and mass balance (MB, in parentheses) are based on 1H NMR using triphenylmethane as internal standard. dThe reaction was performed at −30°C to avoid the formation of uncharacterized side product and to improve the ee values (at 25 °C, an ee value of 72% was observed). eA Rayonet reactor with lamps of approximately 350 nm light output was used for irradiations. fThe yield is based on 1H NMR spectroscopy with an internal standard. 104
It was quite interesting that the substrates 156b and 156c displayed differential reactivity in the absence of sensitizer even though they had similar reacting chromophores (carbonyl and enamide alkene double bond). This implies that these two compound might have different reactive excited state characteristics in the presence and absence of sensitizer.
2.4 Photophysical experiments
To decipher the nature of excited states in 156a-c, we performed several photophysical experiments (vide infra.).
Two sets of compounds were used to for photophysical experiments (Chart 2.3). The first set of compounds (Chart 2.3, a) consist of 156d (cyclic enamide with alkenyl tether), 156e
(acyclic enamide with alkenyl tether), 158 (which has cyclic enamide but no alkenyl or carbonyl tether).
The second set of compounds (Chart 2.3, b) consists of 156b (cyclic enamide with phenyl ketone tether), 156c (cyclic enamide with methyl ketone tether), 159 (a model compound which has carbonyl tether but lacks enamide moiety).
For the synthesis and characterization of 156b-e, and 158 procedure in the reference 21 was followed. 105
(a) (b)
N O O N O
Ph
156d 156b
O
N N O O
156e 156c
N O
O
Ph
158 159
Chart 2.3: Compounds used for photophysical experiments.
2.4.1 Luminescence spectra
To decipher the excited state in the substrates for both normal and transposed Paternò-
Büchi reactions (which has ketone/aldehyde tether), we recorded the luminescence spectra of substrates 156b (enamide with phenyl ketone tether, Figure 2.3b), 156c (enamide with methyl ketone tether, Figure 2.3a), and 159 (model compound 2-phenylacetophenone, Figure 2.3c).
Luminescence spectra was recorded in ethanol glass at 77 K. Model compound 159 (Chart 2.3) 106 lacks the enamide functionality, whereas 156b-c (Chart 2.3) has both enamide alkene double bond and carbonyl group that are essential for Paternò-Büchi reaction.
(b) 1.0 (a) 1.0 ET= 72.8 kcal/mol 0.8 ET= 73.5 kcal/mol 0.8 τ ≈ 8 ms N O 0.6 τp ≈ 0.2 s N O p 0.6 O O 0.4 0.4 Ph 0.2 0.2 156c
Normalized intensity 156b Normalized intensity 0.0 0.0 350 400 450 500 550 600 350 400 450 500 550 600 λ (nm) λ (nm) (c) 1.0
0.8 ET= 72.9 kcal/mol 0.6 τp ≈ 3 ms O 0.4 Ph 0.2 159 Normalized intensity 0.0 350 400 450 500 550 600 λ (nm)
Figure 2.3: Luminescence spectra of 156b, 156c, and 159 measured in ethanol glass measured at
77K for (a) 156c (blue: steady state; black: time resolved), (b) 156b (red: steady state; black: time resolved), (c) 159 (green: steady state; black: time resolved).
Phosphorescence spectra of 156c (enamide with methyl ketone tether, Figure 2.3a) matched with steady state luminescence at 77 K. The phosphorescence lifetime for 156c was found to be 0.2 s, that suggested a pp* character of the triplet excited state in 156c. However, in the case of 156b (enamide with phenyl ketone tether, Figure 2.3b), the phosphorescence spectra at 77 K showed a life time of 8 ms, which is of the same order as the phosphorescence lifetime of
159 (model compound 2-phenylacetophenone, Figure 2.3c) suggesting an np* character in the triplet excited state of 156b. The steady state and time resolved luminescence spectra of 156b 107
(enamide with phenyl ketone tether, Figure 2.3b) showed different features, indicating the possibility of multiple excited state in the case of 156b with low lying np* excited state.
2.4.2 Laser flash photolysis studies
Laser flash photolysis experiments were performed to determine bimolecular quenching rate constant kq for the quenching of xanthone triplets, in the presence of enamide 156b-e and compound 158 and 159 acting as a quencher (Figure 2.4). Excitation wavelength of � = 355 nm and pulse width = 7 ns was employed. Inverse triplet lifetime was determined with the triplet absorption decay monitored at 620 nm for various concentration of enamides. Quenching of thioxanthone triplet was performed with enamide 158.
(a) (b) ) -1 ) s -1 6 s 5 (10 (10 T T 1/ τ 1/ τ
9 -1 -1 156d (kq = 4.0±0.2 ✕ 10 M s ) 158 (k = 1.2±0.1 ¥107 158 (k = 3.8±0.2 ✕ 109 M-1s-1) q q -1 -1 8 -1 -1 M s ) 156e (kq = 9.7±0.5 ✕ 10 M s )
[Enamide] (mM) [158] (mM)
Figure 2.4: Stern-Volmer plot for the determination of bimolecular quenching rate constant for the quenching of (a) xanthone triplet with various concentration of enamides 156d-e, and 158 (b) thioxanthone triplet with various concentration of enamide 158. 108
Analysis of plot in Figure 2.4 a implies that xanthone triplet was efficiently quenched by compound 156d (cyclic enamide with alkenyl tether, Figure 2.4 a) with quenching rate constant
9 -1 -1 of kq = 4 ± 0.2 ´ 10 M s . Hence, enamide 156d is very efficient in quenching the triplet excited state of xanthone (closed to diffusion controlled rate)
However, enamide 156e (acyclic enamide with alkenyl tether, Figure 2.4 a) showed a lower quenching rate constant for the quenching of xanthone triplet by an order magnitude with
8 -1 -1 kq = 9.7 ± 0.5 ´ 10 M s . The lower quenching rate constant may be attributed to the acyclic nature of enamide chromophore. Quite surprisingly we observed that enamide 158 (cyclic enamide with alkyl tether, Figure 2.3-a) also showed efficient quenching of xanthone triplet with
9 -1 -1 a rate constant of kq = 3.8 ± 0.2 ´ 10 M s which was similar to the quenching of xanthone triplets by enamide 156d (cyclic enamide with alkenyl tether, Figure 2.4 a). This implied that the excited state in enamide156d (cyclic enamide with alkenyl tether, Figure 2.4 a) and 158 (cyclic enamide with alkyl tether, Figure 2.4 a) are localized on enamide chromophore.
Quenching of thioxanthone triplets with various concentration of enamide 158 (cyclic enamide with alkyl tether, Figure 2.3-b) showed a lower order of quenching rate constant kq =
1.2 ± 0.1 ´ 107 M-1s-1 (by two orders of magnitude). This was likely due to the lower triplet state energy of thioxanthone (~ 63 kcal/mol) which was not efficient in sensitizing enamide 158 towards Transposed Paternò-Büchi reaction.
109
156c N O 5 N O O
156b 4 156d 156c
9 -1 -1
156c (kq = 3.9±0.2 ✕ 10 M s ) 6 3 9 -1 -1 O 156b (kq = 3.7±0.2 ✕10 M s ) ) x10 ✕ 8 -1 -1 Ph -1 159 (kq = 2.4±0.2 10 M s ) s 6 2 159 (10 T 1/t 1 159
0 1 2 3 4 [Enamide] (mM)
Figure 2.5: Stern-Volmer plot for the determination of bimolecular quenching rate constant for the quenching of (a) xanthone triplet with various concentration of enamides 156b-c, and 159.
Figure 2.5 shows the Stern-Volmer plot for the quenching of xanthone triplet with various concentration of enamide 156b (cyclic enamide with phenyl ketone tether), 156c (cyclic enamide with methyl ketone tether) and 159 (a model compound which has carbonyl tether but lacks enamide moiety). Quenching of xanthone triplets with 156b and 156c was found to be quite efficient with a rate constant of 3.7 ± 0.2 ´ 109 M-1s-1 and 3.9 ± 0.2 ´ 109 M-1s-1 respectively. However, with 159 (a model compound which has carbonyl tether but lacks enamide moiety) showed a lower quenching rate constant of 2.4 ± 0.2 ´ 108 M-1s-1. This may be attributed to the fact that enamide moiety was efficient in quenching xanthone triplets compared to that of carbonyl moiety. 110
2.4.3 Deciphering the excited states in the Paterò-Büchi reaction of substrates 156a-c
from photophysical experiments
Compound 156c (cyclic enamide with methyl ketone tether) underwent photoreaction only upon triplet sensitization and no reaction was observed under direct irradiation. (Table 2.1).
Compound 158 (cyclic enamide with alkyl tether) and 156c (cyclic enamide with methyl ketone tether) featured similar quenching rate constant for the quenching of xanthone triplets. This implied that substrate 156c has excited state localized on enamide chromophore with pp* character. This was also substantiated by the fact that phosphorescence lifetime of 156c at 77K in ethanol glass was in the order of seconds. From phosphorescence spectra, triplet energy computed for 156c was ~ 73.5 kcal/mol which was simi lar to the triplet energy of xanthone (~ 74 kcal/mol). This implies that, xanthone can efficiently sensitize 156c by transferring the triplet energy to enamide chromophore 156c. This generates a pp* excited state of 156c which then adds to the ground state carbonyl group to form 157c. So, unlike traditional
Paternò-Büchi reaction, enamide 156c undergoes transposed Paternò-Büchi reaction where excited state was localized on alkene double bond that adds to the ground state carbonyl functionality.
In the case of phenyl ketone 156b, reaction happens both under sensitization (with xanthone sensitizer) and under direct irradiation. In the presence of xanthone sensitizer, efficient energy transfer from sensitizer to the enamide chromophore of 156b should be possible because it has triplet energy of 72.8 kcal/mol which is just below the triplet energy of xanthone (ET = 74 kcal/mol). But triplet lifetime is in the order of milliseconds which is the characteristic of np* excited state. To explain np* excited state of 156b even though energy transfer happens to enamide chromophore, we proposed intramolecular energy transfer where excited energy from 111 enamide chromophore can transfer to carbonyl group and which then adds to enamide C=C double bond. Under direct irradiation conditions excited state would be localized on carbonyl group hence it undergoes traditional Paternò-Büchi reaction. Excited state of phenyl ketone
156b and methyl ketone 156c under xanthone sensitization can be schematically represented as shown in Figure 2.6
Excited xanthone
Excited xanthone
Energy
N O transfer O Energy N O Ph O transfer
156b 156c
Traditional Paternò-Büchi Transposed Paternò-Büchi reaction reaction
Figure 2.6: Schematic representation of traditional vs transposed Paternò-Büchi reaction
2.5 Computational studies for Transposed vs normal Paterò-Büchi reaction
To evaluate nature of excited states for transposed vs normal Paternò-Büchi reaction we performed computational studies in collaboration with Prof. Raghaven B. Sunoj, IIT Bombay.
Triplet vertical excitation was calculated using linear-response time-dependent density functional theory (TD-DFT) at CAM-B3LYP/6-31+G* level of theory. In all the substrates employed for
Paternò-Büchi reaction, HOMO was found to be localized on enamide moiety. Lowest excited
* * state was found to be of penamide → p character. For Paternò-Büchi reaction substrates p was localized on carbonyl group which indicates that excited state localized on enamide group(156a, 112
* * 156b). However, for phenyl ketone 156c penamide → p and n → p vertical transition has equal energy (78.6 and 80.7 kcal/mol). These computational results are in-line with experimental results.
N O
156g
HOMO LUMO LUMO+2 HOMO LUMO (32.0) HOMO LUMO+2 (38.7)
O N O
156f
HOMO LUMO LUMO+3 HOMO LUMO (15.3) HOMO LUMO+3 (48.0)
Figure 2.7: Frontier molecular orbitals involved in the π enamide → π* triplet excited state of
156g and 156f (generated using an isosurface value of 0.0622). The percentage of contribution of the major transitions is given in parentheses. 113
2.6 Application of Transposed of Paterò-Büchi reaction
From synthetic point of view strategy for transposed vs traditional Paternò-Büchi reaction looks extremely interesting as discussed below.
(a). As the stereochemistry of approach of reacting orbital in transposed vs traditional
Paternò-Büchi reaction are completely different (discussed in section 2.2), just by changing the nature of excited state (np* to pp* or vice versa) different stereoisomers or regio isomers could be synthesized.
(b). One of the challenge in Paternò-Büchi reaction with np* excited state carbonyl system is to control side product formation due to hydrogen abstraction. In np* excited state, electron deficient ‘n’ orbital at oxygen center tends to abstract hydrogen atom much efficiently and competes with [2+2] cycloaddition pathway. But in transposed Paternò-Büchi reaction this challenge could be avoided with pp* excited state of alkene chromophore where hydrogen abstraction is slower.22 114
O O O
H hν + +
108 110 119a 119b [2+2]-adduct
OH OH OH
+ + OH
153 154 155
Hydrogen abstraction products
Scheme 2.13: [2+2] vs competitive hydrogen abstraction product in Paternò-Büchi reaction.
(c). Transposed Paternò-Büchi reaction provides a strategy to sensitize an alkene double bond over carbonyl group. This implies that one can add a C=C double bond to any C=X double bond where X can be any hetero atom (X = O, S, N). This would be really interesting as some reaction such as addition of alkene double bond (C=C) to imine double bond (C=N) is known to be quite challenging. So, strategy of transposed Paternò-Büchi reaction might help us to overcome these challenges. (These aspect are detailed in Chapter 3)
* X hν X
Excited Any double X = C, O, S, N alkene bond
Scheme 2.14: A general representation of addition of excited alkene to any double bond. 115
2.7 Summary
This chapter details strategy for transposed vs normal Paternò-Büchi reaction.
Intramolecular Paternò-Büchi reaction of enamide tethered alkyl ketone/aldehyde and phenyl ketone are explored. With axially chiral substrate efficient axial chiral to point chiral transfer was achieved to get high atropselectivity. Under xanthone sensitization aldehyde and alkyl ketone substrate (156a and 156c) was found to undergo transposed Paternò-Büchi reaction. Direct irradiation did not result any product formation. However direct irradiation of phenyl ketone
(156b) resulted in the formation of photoproduct through normal Paternò-Büchi reaction.
Transposed Paternò-Büchi reaction strategy opens the arena to perform cycloaddition sidestepping hydrogen abstraction reaction (a major side reaction in the excited carbonyl chromophore). It also provides an opportunity to add C=X (X = hetero atom) to activated alkenes.
2.8 Experimental section
2.8.1 General methods
All commercially obtained reagents/solvents were used as received; chemicals were purchased from Alfa Aesar®, Sigma-Aldrich®, Acros organics®, TCI America®, Mallinckrodt®, and Oakwood® Products, and were used as received without further purification. Unless stated otherwise, reactions were conducted in oven-dried glassware under nitrogen atmosphere. 1H-
NMR and 13C-NMR spectra were recorded on Varian 400 MHz (100 MHz for 13C) and on 500
MHz (125 MHz for 13C) spectrometers. Data from the 1H-NMR spectroscopy are reported as chemical shift (δ ppm) with the corresponding integration values. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s 116
(singlet), b (broad), d (doublet), t (triplet), q (quartet), m (multiplet) and virt (virtual). Data for
13C-NMR spectra are reported in terms of chemical shift (δ ppm). High-resolution mass spectrum data in Electrospray Ionization mode were recorded on a Bruker – Daltronics® BioTof mass spectrometer in positive (ESI+) ion mode. HPLC analyses were performed on Waters® HPLC equipped with 2525 pump or on Dionex® Ultimate 3000 HPLC. Waters® 2767 sample manager was used for automated sample injection on Waters® HPLC or Ultimate 3000 sample injector was used for injection on Dionex® HPLC. All HPLC injections on Waters® HPLC were monitored using a Waters® 2487 dual wavelength absorbance detector at 254 and 270 nm or on
Dionex®. HPLC were monitored using a diode array detector (DAD3000125). Analytical and semi-preparative injections were performed on chiral stationary phase using various columns as indicated below. i) Regis® PIRKLE COVALENT (R,R) WHELK–01
a) 25 cm ´ 4.6 mm column for analytical injections
b) 25 cm ´ 10 mm column for semi-preparative injections ii) CHIRACEL® OD-H
a) 0.46 cm ´ 25 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections iii) CHIRALPACK® IC
a) 0.46 cm ´ 25 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections 117 iv) CHIRALPAK® AD-H
a) 0.46 cm ´ 15 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections
Masslynx software version 4.1 was used to monitor/analyze the HPLC injections and to process HPLC traces. Igor Pro® Software version 6.0 was used to process the HPLC graphics.
UV-Vis spectra were recorded on Shimadzu 2501PC UV-Vis spectrometer using UV quality fluorimeter cells (with range until 190 nm) purchased from Luzchem. When necessary, the compounds were purified by combiflash equipped with dual wavelength UV-Vis absorbance detector (Teledyn ISCO) using hexanes:ethyl acetate as the mobile phase and Redisep® cartridge filled with silica (Teledyne ISCO) as stationary phase. In some cases, compounds were purified by column chromatography on silica gel (Sorbent Technologies®, silica gel standard grade: porosity 60 Å, particle size: 230 x 400 mesh, surface area: 500 – 600 m2/g, bulk density: 0.4 g/mL, pH range: 6.5 – 7.5). Unless indicated, the Retardation Factor (Rf) values were recorded using a 5-50% hexanes:ethyl acetate as mobile phase and on Sorbent Technologies®, silica Gel
TLC plates (200 mm thickness w/UV254).
2.8.2 Computational methods
All calculations were performed using the Gaussian09 suite of quantum chemical program.1 We have employed the long-range corrected Coulomb-attenuated method (CAM) in conjunction with the B3LYP functional for the present investigation.2 Pople’s 6-31+G* basis set was used for all atoms.3 Solvent effects (acetone) were incorporated using the polarizable continuum model (PCM)4 in its corrected linear response (cLR)5 version for the excited states.
Ground state geometries were first optimized at the CAM-B3LYP/6-31+G* functional in 118 conjunction with Pople’s 6-31+G* basis set. All geometries were characterized as minima by
Hessian calculations. Next, TD-DFT calculations were performed using the ground state geometry at the CAM-B3LYP/6-31+G* level of theory to determine the vertical excitation energies. Nature of the excited state was determined by analyzing the coefficient of contributing transitions and through the visual inspection of the participating molecular orbitals in each of the transitions.
2.8.3 Photophysical experiments
Spectrophotometric solvents (Sigma-Aldrich®) were used when ever necessary unless mentioned otherwise. UV quality fluorimeter cells (with range until 190 nm) were purchased from Luzchem®. Absorbance measurements were performed using a Shimadzu® UV-2501PC
UV-Vis spectrophotometer. Laser flash photolysis (LFP) experiments employed the pulses from a Spectra Physics GCR-150-30 Nd:YAG laser (355 nm, ca 5 mJ/pulse, 7 ns pulse length) and a computer controlled system that has been described elsewhere.6
2.8.4 Synthesis of tert-butyl-2,4,6-trimethylaniline carbamate
Boc NH2 HN (Boc)2O THF, 4 h, reflux
95% 147 148
Scheme 2.15: Synthesis of tert-butyl-2,4,6-tert-butylcarbamate 148.
The tert-butyl-phenyl-carbamate derivative 149 was synthesized according to a procedure reported in the literature. A mixture of aniline 147 (2.0 g, 1.0 equiv.) and (Boc)2O (1.2 equiv.) in a dry THF (20 mL) was refluxed for 4 h. After the reaction, the solution was cooled to room 119 temperature, DI water (50 mL) and ethyl acetate (20 mL) was added, stirred for 10 min and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 ´ 15 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhyd. Na2SO4, filtered and the solvent was removed under reduced pressure to get the crude product. The crude product was purified by combiflash using hexanes: ethyl acetate mixture.
Boc HN
148
Rf = 0.50 (80% hexanes: 20% ethyl acetate) for 149, (Yield = 87%).
1 H-NMR (400 MHz, CD3OD, δ ppm): 6.83 (s, 2H), 2.21 (s, 3H), 2.16 (s, 6H) and 1.48 (s, 9H)
13 C-NMR (100 MHz, CD3OD, δ ppm): 159.7, 140.2, 139.8, 135.8, 132.4, 83.1, 31.6, 23.8 and
21.1.
2.8.5 Synthesis of tert-butyl 2,4-dimethyl-6-(tert-butylacetate)-N-Boc-aniline 142
Boc Boc HN HN sec-BuLi, -45 oC, THF, 15 min. O-t-Bu
(Boc)2O, 5 min. O
95% 148 149
Scheme 2.16: Synthesis of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149.
To a solution of Boc protected aniline derivative 148 (2.0 g, 8.50 mmol) in dry THF (25 mL) at -45 oC, sec-BuLi (1.4 M in cyclohexanes, 1.4 g, 21.2 mmol) was added. The solution was stirred for 15 min followed by the addition of a) Boc anhydride (2.6 mL, 25.5 mmol) and stirred 120
o for 5 min. After the reaction, the solution was cooled to 0 C, quenched with saturated NH4Cl solution extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhyd. Na2SO4, filtered and the solvent was removed under reduced pressure to get the crude product. The crude product was purified by combiflash using hexanes:ethyl acetate mixtures.
121
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.91 (s, 1H), 6.83 (s, 1H), 6.62 (bs, 1H), 3.46 (s, 2H), 2.22
(s, 3H), 2.197 (s, 3H), 1.47 (s, 9H) and 1.42 (s, 9H). -Bu t O O Boc HN
*
= solvent *
Figure 2.8: 1H-NMR of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149.
122
13 C-NMR (100 MHz, CDCl3, δ ppm): 171.7, 153.97, 136.5, 132.2, 131.95, 130.8, 128.98, 81.3,
79.6, 39.9, 28.5, 28.2, 21.0 and 18.5.
* -Bu t O O Boc HN
= solvent *
Figure 2.9: 13C-NMR of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149. 123
HRMS-ESI (m/z) ([M + Na]):
Calculated : 358.1994
Observed : 358.1994
|Dm| : 0.0 ppm
Boc HN O
O
Figure 2.10: HRMS of tert-butyl-2,4,6-dimethyl-6-(tert-butylacetate)-N-boc-aniline 149.
124
2.8.6 Synthesis of 2-amino-(3,5-dimethyl)-phenylethanol 150
Boc HN NH2 O-t-Bu OH 1. LiAlH4, THF, rt, 2 h O 2. H2O, Reflux, 6 h 85% 149 150
Scheme 2.17: Synthesis of 2-amino-(3,5-dimethyl)-phenethylalcohol 150.
o To a slurry of LiAlH4 (0.11 g, 2.95 mmol) in dry THF (15 mL) at 0 C slowly added a solution of (2,4-dimethyl-6-(2-oxo-2-phenylethyl)-Boc derivative 149 (1.0 g, 2.95 mmol) over a period of 10 min. After the addition, the mixture was allowed to warm to room temperature and further stirred for 2 h. After the reaction, the solution was cooled to 0 oC, quenched with saturated NH4Cl solution extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhyd. Na2SO4, filtered and the solvent was removed under reduced pressure to get the crude product. The crude product was directly taken to the next step.
The deprotection of Boc group was performed by refluxing the boc protected alcohol derivative in water for 6 h (50 mL). After 6 h, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 x 40 mL) The combined organic layer was dried over Na2SO4, filtered and concentrated to get the crude. The crude was purified by combiflash to get the pure product.
125
Rf = 0.25 (50% hexanes: 50% ethyl acetate), Yield for 150= 65%
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.82 (s, 1H), 6.76 (s, 1H), 3.799 (t, J = 6.5 Hz, 2H), 3.62
(bs, 3H), 2.73 (t, J = 6.5 Hz, 2H), 2.26 (s, 3H) and 2.16 (s, 3H). OH 2 NH
Figure 2.11: 1H-NMR of 2-amino-(3,5-dimethyl)-phenethylalcohol 150. 126
13 C-NMR (100 MHz, CDCl3, δ ppm): 140.7, 129.9, 129.2, 127.9, 124.3, 123.2, 60.1, 35.3, 20.7 and 18.0.
* OH 2 NH
= solvent *
Figure 2.12: 13C-NMR of 2-amino-(3,5-dimethyl)-phenethylalcohol 150. 127
HRMS-ESI (m/z) ([M + Na]):
Calculated : 188.1051
Observed : 188.1051
|Dm| : 0.0 ppm
NH2 OH
Figure 2.13: HRMS of 2-amino-(3,5-dimethyl)-phenethylalcohol 150.
128
2.8.7 Synthesis of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isopropyl) ethanol 151
NH2 TIPSCl, NH2 OH Immidazole DMF 70 °C, 2 h OTIPS 95%
150 151
Scheme 2.18: Synthesis of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151
The TIPS protected aniline 153 was synthesized following a procedure reported in the literature. To a solution of corresponding aniline 151 (1.0 g, 1.0 equiv.) and imidazole (2.4 equiv.) in dry DMF (10 mL) at room temperature, triisopropylsilyl chloride (TIPSCl, 1.2 equiv.) was added. The resulting mixture was heated to 70 oC and maintained until complete consumption of starting material. After the reaction, the mixture was cooled to room temperature, added DI water (40 mL) and extracted with diethyl ether (3 ´ 15 mL). The combined organic layer was washed with DI water (15 mL), brine solution (15 mL), dried over anhyd. Na2SO4, filtered and the solvent was removed under reduced pressure to get the crude product. The crude product was purified by combiflash using hexanes: ethyl acetate mixture.
129
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.83 (s, 1H), 6.79 (s, 1H), 4.02-3.98 (m, 2H), 3.86 (bs, 2H),
2.89-2.83 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) and 1.12 (s, 21H). OTIPS 2 NH
= solvent *
Figure 2.14: 1H-NMR of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151. 130
13 C-NMR (100 MHz, CDCl3, δ ppm): 151.2, 139.4, 139.1, 137.1, 134.5, 132.4, 74.8, 45.8, 30.5,
28.1, 27.9 and 22.1.
* OTIPS 2 NH
= solvent *
Figure 2.15: 13C-NMR of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151. 131
HRMS-ESI (m/z) ([M + Na]):
Calculated : 344.2386
Observed : 344.2386
|Dm| : 0.0 ppm
NH2 OTIPS
Figure 2.16: HRMS of 2-amino-(3,5-dimethyl)-phenyl-(O-tri-isoropyl)ethanol 151.
132
2.8.8 Synthesis of imide derivative 153
1.Anhy. Toluene O O NH2 45 °C, 2 h N 2.AcOH, AcONa. Reflux, 2 h OTIPS OTIPS O O O 70%
151 152 153
Scheme 2.19: Synthesis of imide derivative 153.
To the solution of aniline 151 (11.4 g, 35.4 mmol) in dry toluene (250 mL) added 2,2- dimethyl succinic anhydride 152 (5 g, 39.0 mmol) and the solution was stirred at 45 °C for 2 h.
After 2 h toluene was evaporated by using rotary evaporator. To the crude mixture added acetic acid (250 mL), sodium acetate (3.7 g, 39 mmol) and was refluxed for 2h. After the reaction, the mixture was cooled to room temperature, added DI water (100 mL) and extracted with diethyl ether (3 ´ 50 mL). The combined organic layer was washed with DI water (50 mL), brine solution (50 mL), dried over anhyd. Na2SO4, filtered and the solvent was removed under reduced pressure to get the crude product. The crude product was purified by combiflash using hexanes: ethyl acetate mixture to get 70% of isolated product.
133
Rf = 0.2 (90% hexanes: 10% ethyl acetate), Yield for 153 = 70%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.02 (s, 1H), 6.96 (s, 1H), 3.72 (t, J= 8.0 Hz, 2H), 2.71 (s,
2H), 2.60-2.56 (m, 2H), 2.28 (s, 3H), 2.03 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H) and 1.02-1.01 (m,
21H). O N
O
TIPSO
*
= solvent *
Figure 2.17: 1H NMR of imide derivative 153. 134
13 C-NMR (100 MHz, CDCl3, δ ppm): 182.7, 175.3, 139.4, 139.5, 135.6, 130.1, 129.6, 127.7,
63.8, 44.2, 40.8, 35.6, 26.0, 21.3, 18.2, 18.1, 17.9 and 12.2.
* O N
O
TIPSO
= solvent *
Figure 2.18: 13C-NMR of imide derivative 153. 135
HRMS-ESI (m/z) ([M + Na]):
Calculated : 454.2753
Observed : 454.2743
|Dm| : 1.0 ppm
O N O OTIPS
Figure 2.19: HRMS of imide derivative 153.
136
2.8.9 Synthesis of imide derivative 154
O N O 1. DIBAL, DCM, N O -78 °C, 30 min OTIPS 2. MsCl, Et3N, DCM, 0 oC, 2 h OTIPS
75% 153 154
Scheme 2.20: Synthesis of enamide derivative 154
To a solution of corresponding imide 153 (2.0 g, 1.0 equiv.) in DCM (25 mL) under N2 atmosphere at -78 oC, DIBAL (25% w/w in hexanes, 1.3 equiv.) was added. The mixture was stirred at -78 oC for 30 min. The reaction mixture was quenched with DI water (10 mL) followed by the addition of aq. 2N NaOH solution (10 mL). The reaction mixture was slowly warmed to room temperature and the mixture was poured into saturated solution of Rochelle’s salt (sodium potassium tartarate, 200 mL). The aqueous layer was extracted with DCM (3 ´ 75 mL). The combined organic layer was dried over anhyd. Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product. The crude product was directly taken to next step without further purification.
To the crude product from above reaction dissolved in DCM (75 mL) at 0 oC, methanesulfonyl chloride (1.3 equiv.) and triethylamine (2.6 equiv.) was added. The resulting solution was stirred at 0 oC for 2 h. After the reaction, DI water (50 mL) was added, stirred for 10 min and the layers were separated. The aqueous layer was extracted with of DCM (2 ´ 20 mL).
The combined organic layer was washed with brine solution (30 mL), dried over anhyd. Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash using a hexanes:ethyl acetate mixtures.
137
Rf = 0.30 (90% hexanes: 10% ethyl acetate), Yield for 154= 75%
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.98 (s, 1H), 6.91 (s, 1H), 6.29 (d, J = 4.8 Hz, 1H), 5.46 (d,
J = 4.8 Hz, 1H), 3.79-3.75 (m, 2H), 2.699-2.66 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 1.29 (s, 3H),
1.28 (s, 3H) and 1.06-0.98 (m, 21H). O N
TIPSO
*
= solvent *
Figure 2.20: 1H-NMR of enamide derivative 154. 138
13 C-NMR (100 MHz, CDCl3, δ ppm): 181.9, 138.2, 137.4, 136.5, 132.1, 131.8, 129.8, 129.4,
117.9, 64.0, 46.2, 35.5, 23.8, 23.7, 21.2, 18.2, 18.0 and 12.2.
O * N
TIPSO
= solvent *
Figure 2.21: 13C-NMR of enamide derivative 154. 139
HRMS-ESI (m/z) ([M + Na]):
Calculated : 438.2804
Observed : 438.2804
|Dm| : 0.0 ppm
N O OTIPS
Figure 2.22: HRMS of enamide derivative 154.
140
2.8.10 Synthesis of alcohol derivative 155
N O TBAF, THF, N O reflux, 2 h OH
OTIPS 75%
154 155
Scheme 2.21: Synthesis of alcohol derivative 155.
To a solution of TIPS protected enamide derivative 154 (2.0 g, 1.0 equiv.) in THF (20 mL) under N2 atmosphere and at room temperature, TBAF (1M in THF, 1.1 equiv.) was added. The resulting solution was heated to reflux and maintained until complete consumption of starting material. After the reaction, the mixture was cooled to room temperature, diluted with DI water
(30 mL) and extracted with ethyl acetate (2 ´ 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhyd. Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash using a hexanes:ethyl acetate mixtures.
141
Rf = 0.20 (50% hexanes: 50% ethyl acetate), Yield for 155= 75%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.93 (s, 2H), 6.27 (d, J = 4.8 Hz, 1H), 5.47 (d, J = 4.8 Hz,
1H), 3.65 (q, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.50 (t, J = 5.8 Hz, 1H), 2.26 (s, 3H), 2.06
(s, 3H) and 1.26 (s, 6H). O N
HO
*
= solvent *
Figure 2.23: 1H-NMR of alcohol derivative 155. 142
13 C-NMR (100 MHz, CDCl3, δ ppm): 182.7, 138.7, 137.3, 136.6, 132.1, 131.5, 130.1, 129.1,
118.4, 62.7, 46.4, 34.9, 23.7, 23.6, 21.3 and 18.0.
* O N
HO
= solvent *
Figure 2.24: 13C-NMR of alcohol derivative 155. 143
HRMS-ESI (m/z) ([M + Na]):
Calculated : 282.1470
Observed : 282.1470
|Dm| : 0.0 ppm
N O OH
Figure 2.25: HRMS of alcohol derivative 155. 144
2.8.11 Synthesis of aldehyde derivative 156a
N O DMP, DCM, N O rt, 2 h OH O
92%
155 156a
Scheme 2.22: Synthesis of aldehyde derivative 156a
To a slurry of Dess-Martin periodinane (DMP) (1.2 equiv.) in DCM (20 mL) at 0 oC, a solution of corresponding alcohol derivative 155 (500 mg, 1.0 equiv.) in DCM (5 mL) was added. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with 1N NaOH solution (10 mL) and the mixture was extracted with DCM (2 ´ 15 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhyd.
Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product.
The crude product was purified by combiflash using a hexanes:ethyl acetate mixture to get the title product.
145
Rf = 0.60 (50% hexanes: 50% ethyl acetate), Yield for 156a = 92%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 9.55-9.53 (m, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.23 (d, J =
4.8 Hz, 1H), 5.44 (d, J = 4.8 Hz, 1H), 3.52-3.40 (m, 2H), 2.26 (s, 3H), 2.09 (s, 3H) 1.24 (s, 3H) and 1.23 (s, 3H). O N
O
Figure 2.26: 1H-NMR of aldehyde derivative 156a. 146
13 C-NMR (100 MHz, CDCl3, δ ppm): 199.3, 181.9, 139.0, 136.96, 132.6, 131.4, 131.2, 131.1,
129.8, 118.3, 47.2, 46.1, 23.7, 23.3, 21.2 and 18.4.
O * N
O
= solvent *
Figure 2.27: 13C-NMR of aldehyde derivative 156a. 147
HRMS-ESI (m/z) ([M + Na]):
Calculated : 280.1313
Observed : 280.1313
|Dm| : 0.0 ppm
N O O
Figure 2.28: HRMS of aldehyde derivative 156a.
148
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.93-7.91 (m, 2H), 7.53-7.49 (m, 1H), 7.43-7.39 (m, 2H),
6.997 (s, 1H), 6.896 (s, 1H), 6.26 (d, J = 4.8 Hz, 1H), 5.31 (d, J = 4.8 Hz, 1H), 4.34 (d, J = 17.4
Hz, 1H), 4.01 (d, J = 17.4 Hz, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.22 (s, 3H) and 0.96 (s, 3H). Ph O O N
Figure 2.29: 1H-NMR spectra of 156b. Adapted from reference 23. 149
13 C-NMR (100 MHz, CDCl3, δ ppm): 197.6, 181.8, 138.7, 136.9, 136.4, 133.8, 133.5, 132.5, 131.9, 131.0, 129.9, 128.8, 128.4, 117.7, 46.0, 42.5, 23.8, 23.5, 21.3 and 18.1.
* Ph O O N
= solvent *
Figure 2.30: 13C-NMR spectra of 156b. Adapted from reference 23.
150
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 358.1621
Observed : 358.1623
|Dm| : 0.6 ppm
N O Ph
O
Figure 2.31: HRMS of aldehyde derivative 156b. Adapted from reference 23. 151
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.27-7.24 (m, 2H), 7.19-7.17 (m, 1H), 7.12-7.09 (m, 1H), 6.39 (d, J = 4.8 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 3.65 (s, 2H), 2.04 (s, 3H) and 1.22 (s, 6H).
O O N
Figure 2.32: 1H-NMR spectra of 156c. Adapted from reference 23. 152
13 C-NMR (100 MHz, CDCl3, δ ppm): 205.2, 181.3, 136.2, 132.2, 131.7, 131.3, 128.3, 126.8, 118.2, 47.3, 46.2, 29.5 and 23.5.
*
O O N
*= solvent
Figure 2.33: 13C-NMR spectra of 156c. Adapted from reference 23. 153
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 266.1151
Observed : 266.1146
|Dm| : 1 .9 ppm
N O
O
Figure 2.34: HRMS of 156c. Adapted from reference 23. 154
2.8.12 Computational studies of enamides
The orbital contours for 156g and 156f in the following Figure 2.29. It can be noticed that two of the lower energy unoccupied orbitals, LUMO and LUMO+2 for 156g, are the p* molecular orbitals of the aryl and the cyclic enamide fragments respectively. In the lowest triplet excited state, the contribution of LUMO and LUMO+2 is about 70.7% in 156g. The S0®T1 excitation in the case of 156f is found to be from the HOMO (penamide) to LUMO+3 (p*C=O)
a) Frontier Molecular Orbitals involved in the lowest energy S0®T1 state of 156g
N O
156g
HOMO LUMO LUMO+2
HOMO ® LUMO (32.0)
HOMO ® LUMO+2 (38.7)
b) Frontier Molecular Orbitals involved in the lowest energy S0®T1 state of 156f 155
O N O
156f
HOMO LUMO LUMO+3
HOMO ® LUMO (15.3)
HOMO ® LUMO+3 (48.0)
Figure 2.35: Frontier molecular orbitals involved in the penamide®p* triplet excited state of 156g and 156f (generated using an isosurface value of 0.0622). The percentage of contribution of the major transitions is given in parentheses. 156
Table 2.2: Vertical Excitation Energies (kcal/mol) of Different Transitions Calculated at the cLR-PCM(acetone)/TD-CAM-B3LYP/6-31+G* Level of Theory.
Chromophore penamide®p* palkene®p* n®p* 156d 78.4 91.7 116.4 156g 78.1 91.5 115.9 156e 80.0 91.7 173.5 a 156b 78.6 - 80.7 156f 78.5 - 88.4 156c 79.0 - 90.3 156a 78.3 88.6 a Lower energy states with smaller n®p* contribution were also found.
157
Table 2.3: Frontier Molecular Orbitals Involved in the Lowest Energy penamide®p* Excited State along with the Major Contributing Transitions for 156d and 158.
N O
156d
HOMO ®LUMO+1 (44.1) a HOMO LUMO+1 LUMO+2 HOMO ®LUMO+2 (24.5)
N O
158
HOMO ®LUMO (33.6) HOMO LUMO LUMO+1 LUMO+2 HOMO ® LUMO+1 (19.2)
HOMO ® LUMO+2 (16.8) a Percentage contribution of each transition is mentioned in parenthesis. b
158
Table 2.4: Frontier Molecular Orbitals Involved in the Lower Energy Excited State along with the Major Contributing Transitions for 140a-c, 140f.
N O O
Ph
156b HOMO penamide®p*
HOMO®LUMO+2 (32.0)
HOMO®LUMO+4 (20.4)
LUMO LUMO+2 LUMO+4 n®p*
HOMO ®LUMO (50.0)
N O O
HOMO LUMO+3 156c 159
penamide®p*
HOMO®LUMO+3 (54.0)
O N O
156f HOMO LUMO+3
N O O
156a
penamide®p*
HOMO®LUMO+3 (34.9) HOMO LUMO+1 LUMO+2 LUMO+3
HOMO®LUMO+1 (16.0)
HOMO®LUMO+2 (15.2) 160
2.8.13 Photophysical studies of enamides 134b-e,134g,148
N O N O N O
156d 156g 156e
N O N O O O O
Ph Ph
156c 159 156b
Chart 2.4: Enamides and sensitizers employed for photophysical studies.
Bimolecular quenching rate constants of xanthone and thioxanthone triplets were determined by laser flash photolysis. Acetonitrile solutions of xanthone and thioxanthone were prepared such that the absorption at the excitation wavelength (355 nm) was 0.3 (1 cm path length). To these solutions appropriate amounts of enamides were added. The solutions were deoxygenated by argon purging. Absorbance decay traces were recorded at 620 nm (sensitizer triplet absorption) and fitted to a mono-exponential function. The resulting observed triplet lifetimes (tT) were plotted against the enamide concentration. The bimolecular quenching rate constants (kq) were obtained from the slope of these plots (Figure 2.3) and are summarized in
Table 2.5. 161
) 156e -1 156d cm
-1 159 (M ε
Wavelength (nm)
Figure 2.36: UV/Vissible spectrum of 156e,156d and 149 measured in MeCN.
Table 2.5: Bimolecular quenching rate constant (kq) for the quenching of the sensitizer triplet states by enamides.
-1 -1 Entry Enamide Sensitizer kq (M s ) 1 156d Xanthone 4.0±0.2 ´ 109 2 156e Xanthone 3.8±0.2 ´ 109 3 159 Xanthone 9.7±0.5 ´ 108 4 159 Thioxanthone 1.2±0.1 ´ 107
162
2.8.14 Procedure for photoreaction of 156a
h ν O O N O Acetonitrile, Xanthone (30 mol%) N O
H rt, 0.5 , N2
156a 157a
Scheme 2.23: Synthesis of photoproduct 157a.
A solution of optically pure atropisomeric or achiral enamide 156a (~1.5-2.3 mM or ~1 mg/2 mL) in acetonitrile and 30 mol % sensitizer (xanthone) in Pyrex tube placed in a merry-go- round (8 x 10 mL test tubes) were irradiated in a Rayonet reactor for given time period at room temperature (25 °C). After irradiation, the solvent was evaporated under reduced pressure and the photoproducts were isolated Combiflash and characterized by NMR spectroscopy, mass spectrometry and HPLC. HPLC analysis of the photolysate on chiral stationary phases gave the optical purity of the photoproducts. 163
Rf = 0.20 (80% hexanes:20% ethyl acetate) for 157a
H-NMR (400 MHz, CDCl3, δ ppm): 6.95 (s, 1H), 6.76 (s, 1H), 5.33-5.30 (m, 1H), 4.89-4.881 (d,
J = 4.8 Hz, 1H), 4.20-4.18 (t, J = 5.0 Hz, 1H), 3.08-3.02 (m, 1H), 2.69-2.63 (d, J = 15 Hz, 1H),
2.27 (s, 3H), 2.25 (s, 3H), 1.21 (s, 3H) and 1.16 (s, 3H). O N
O
*
= solvent *
Figure 2.37: 1H-NMR of photoproduct 157a. 164
13 C-NMR (100 MHz, CDCl3, δ ppm): 179.4, 137.1, 134.9, 132.7, 132.5, 129.7, 127.1, 84.9, 81.4,
55.6, 45.5, 33.9, 22.0, 21.3, 17.7, 16.2
* O N
O
* = solvent
Figure 2.38: 13C-NMR of photoproduct 157a. 165
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK AD-H
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 95:5
Flow rate : 1.0 mL/min
Retention times (min) : ~ 20.0 [(A)-157a] and ~ 22.0 [(B)-157a]
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Benzophenones. Photochem. Photobiol. Sci. 2008, 7, 1332–1336. 167
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169
3 CHAPTER 3: AZA PATERNÒ-BÜCHI REACTION
Introduction
Even though [2+2] photocycloaddition of alkene to carbonyl group, thiocarbonyl to alkene, or alkene to alkene are very well known in the literature, the corresponding aza equivalent reaction i.e. [2+2]-photocycloaddition of imine to alkene double bond is scarcely reported
(Scheme 3.1).1
X hν X Well known! X = C, O, S
X X N hν N Not well known ?! X
Scheme 3.1: Imine [2+2] photocycloaddition vs alkene.
This challenge of imine [2+2]-photocycloaddition was due to several competing reaction pathways that are possible for imines upon excitation. Imine systems upon excitation with a light of a suitable wavelength undergos photoisomerization, photoreduction, photoalkylation, photoelimination, photocyclization, photofragmentation, photorearrangemnet etc (Figure. 3.1)
Material in this chapter was co-authored by Elango Kumarasamy (EK), Sunil Kumar Kandappa (SK), Ramya Raghunathan (RR) Steffen Jockusch (SJ) and J. Sivaguru (JS).14 EK, and SK in consultation with JS synthesized compounds for the study. SJ in consultation with JS carried out the photophysical experiments. EK and SK contributed equally to the manuscript.
170
Under such conditions designing strategies for exclusive [2+2]-photocycloaddition involving imine and alkenes bypassing all other unwanted reaction is quite challenging. This chapter deals with developing a novel strategy for exclusive [2+2]-photocycloaddition of imine double bond to alkene double bond, a process we termed as Aza Paternò-Büchi reaction.
Photoisomerization
Photoreduction
3 Photorearrangement R C N R2 R1
Photoalkylation
Photoelimination Photocyclization
Figure 3.1: Various pathways for photoreaction of imines. 171
3.1 Excited state characteristics of imine double bond
3.1.1 Photoisomerization
Imines undergo E-Z isomerization under photochemical conditions. This transformation has been found to be a major deactivation pathway for excited imines (Scheme 3.2).
3 R1 hν R1 R N N 2 2 R R3 R syn anti
Scheme 3.2: Schematic representation for the photoisomerization of imines.
Padwa and co-workers explored photoisomerization of oxime ethers (Scheme 3.3).2
Irradiation of N-(O-methyl) acetophenone oxime 160 in pentane solution with 250 nm light resulted in syn-anti isomerization with a photostationary state (Schme3.3). The syn-anti ratio at the photostationary state was 2.2. Both direct irradiation and sensitized irradiation resulted in photoisomerization. The quantum yield for syn → anti and anti → syn interconversion was 0.30 and 0.27 respectively.
hν ~ 250 nm Ph Pentane Ph OCH3 N N H3C OCH3 H C E/Z = 2.2 3 syn-160 anti-160
Scheme 3.3: Photoisomerization of N-(O-methyl) acetophenone oxime 160.
The same group also explored photoisomerization N-(O-methyl)-2-acetonaphthone oxime
161.3 Irradiation of oxime (Scheme 3.4) ether 161 with 310 nm light in pentane solution resulted in a photostationary state with a syn/anti ratio that was found to vary with the reaction concentration. At lower concentrations, syn isomer predominated and at higher concentration 172 anti was observed predominantly. It was proposed that isomerization happened through an excited singlet state that decayed to ground state through collisional quenching. At higher concentration formation of an exciplex with the ground state reacting partner was proposed.
hν ~ 310 nm Pentane OCH3 N syn/anti = N OCH 3 conc. dependent CH3 CH3 syn-161 anti-161
Scheme 3.4: syn – anti photoisomerization of N-(O-methyl)2-naphthol oxime 161.
3.1.2 Photoreduction
Short and co-workers demonstrated photoreduction of benzophenone imine 162 in ethanol at 350 nm utilizing4 10 mol% of iodine in isopropyl alcohol as the sensitizer (Scheme
3.5). The reaction was proposed to occur from an np* excited state of imine that was analogous to that of excitation of benzophenone for hydrogen abstraction. This mechanism was disproved by
Padwa and co-workers who proposed that this photoreduction does not involve excited state of imine. Instead, reaction involved the formation of an aldehyde intermediate that underwent excitation followed by abstracts hydrogen atom abstraction from isopropanol and subsequently adding the imine in the ground state leading to the formation of amino radical intermediate r-164.
This intermediate then underwent disproportionation to form reduced product.
hν ~ 350 nm NH OH 10 mol% I2/ IPA NH2 O NH2 Ph Ph Ph Ph Ph Ph 162 163 164 17 r-164
Scheme 3.5: Photoreduction of benzophenone imine 162. 173
3.1.3 Photoalkylation
Nicodem and coworker demonstrated photoalkylation of indolene 165 in acetone- methanol mixture (Scheme 3.6).5 Acetone from its excited state abstracts hydrogen from methanol to form carbon centered radical to form r-167 that added across imine double bond to form 166.
hν CH OH CH3 3 CH3 167 Acetone CH2OH N N r-167 165 O 166
Scheme 3.6: Photoalkylation of indolene 165.
3.1.4 Photoelimination
Imine system that has alkyl group with g-hydrogen attached to imine carbon can undergo elimination with a mechanism similar to Norish Type II reaction. Stermitz and Wei reported photoelimination of 2-alkylquinoline 168 (Schme 3.7).6 Imine 168 in its np* excited sate abstracted g-hydrogen through a cyclic transition state followed by elimination to form exocyclic product 170 that rearranged back to quinolone derivative 169. 174
hν~ 300 nm Benzene R N 60 h, 45% conversion N CH3 168 169 hν
*
α N N H H β N γ H R R
168* 170
Scheme 3.7: Photoelimination of 2-alkylquinoline 168.
3.1.5 Photofragmentation
Compound 171 and 174 that features an imine functionality underwent a-cleavage upon photoexcitation (Scheme 3.8). Koach and co-workers showed a-cleavage of 2-phenyl-2- oxazoline-4-one 171 which upon irradiation in benzene solution gave 4-phenyl-4-oxazoline-2- one 173 (Scheme 3.8).7 They reported that the reaction involved an np* singlet excited state localized on the imine chromophore. However, structurally related a,b-unsaturated carbonyl compounds (enones) reacted from its np* excited state resulting in photocycloaddition. This difference in reactivity was explained based on high singlet np*excited state energy of the imine that resulted in a-cleavage. Similarly, when 2-ethoxy-2-oxazoline-4-one 174 was irradiated in benzene solution that resulted, a-cleavage leading the formation cyclopropyl isocyanate 175 upon treatment with tert-butyl alcohol led to the formation of corresponding carbamate 176
(Scheme 3.8). 175
O Ph h O α-cleavage ν C Benzene N Rearrangement N N O O Ph O Ph Ph
171 172 173
O O hν C α-cleavage Benzene t-BuOH N N NHCO2-t-Bu O O OC2H5 O OC2H5 OC2H5
174 175 176
Scheme 3.8: a-cleavage of cyclic imine derivatives 171 and 174.
3.1.6 [2+2]-Photocycloaddition of imines
Despite the challenge associated with excited nature of imine due to various possible side reactions, there were few reports of successful imine [2+2]-photocycloaddition.8,9 However, these examples were substrates specific and had some constraints in the structure. For example, to avoid the major deactivation pathways such as E/Z isomerization of the imines excited state, imine chromophore should be a part of five or six membered ring. It also should have electron withdrawing group to favor photocycloaddition to overcome potential electron transfer deactivation of the excited state of the imine functionality.
Tsuge, Tashiro and Oe in 1968 reported the first imine [2+2]-photocycloaddition. They irradiated benzene solution of 2,5-diphenyl-2,3-4-oxadiazole 177 and indene 178 to get azetidine
179 (Scheme 3.9).10 176
hν Ph Ph Ph O Ph Benzene O + N N N N
177 178 179
Scheme 3.9: Imine [2+2]-photocycloaddition of 2,5-diphenyl-2,3-4-oxadiazole 177.
Koach and co-workers demonstrated imine [2+2] photocycloaddition for the reaction of
3-ethoxyisoindolone 180 with 1,1-dimethoxy ethylene 181 to get azetidine derivatives 182
(Scheme 3.10).7 They were also successful in adding 3-ethoxyisoindolone imine 180 to cyclohexene 183 leading to 184 (Scheme 3.10). A limitation of the strategy was that the reaction was unsuccessful with electron deficient alkene such as fumaranonitrile. In addition, the reaction necessitated the requirements of a stabilized cyclic imine for successful photochemical reaction.
O O CH2 hν N N + CH3O OCH3 C2H5O OCH3 OC2H5 CH3O 180 181 182
O O N hν + N OC2H5 C2H5O
180 183 184
Scheme 3.10: Imine [2+2]-photocycloaddition of 3-ethoxyisoindolone 180.
Irradiation of 2-phenyl-2-oxazoline-4-one 171 with 1,1-demethoxy ethylene 181 resulted in the formation of azetidine photoproduct 185 (Scheme 3.11). But, the reaction of 1,1- 177 demethoxy ethylene 181 with oxazinone derivative 186 failed to result in the formation of any photoproduct (Scheme 3.12). Oxazinone 186 was formed to undergo dimerization in the presence of protic solvent such as isopropyl alcohol.7,11
O hν O CH 2 Benzene N N + CH O OCH3 O 3 O OCH3 Ph Ph OCH3
171 181 185
Scheme 3.11: Imine [2+2]-photocycloaddition of 3-ethoxyisoindolone.
O O hν O CH2 O + X N N OCH CH3O OCH3 3 OCH3
186 181 187
O O O O O hν O HN O O + N (CH3)2CHOH NH O NH HN 163 O 186 188a 188b
Scheme 3.12: Photoreaction of oxazinone derivative 186.
Based on these results (Scheme 3.11 – 3.12) the authors concluded that imine dimerization occurred if the lowest excited state in imine chromophore is of pp* in nature. If it is of np*character, then it underwent typical hydrogen atom abstraction e.g. as in the case of 186 in protic solvent. 178
Sampedro and co-workers carried out computational studies for imine photocycloaddition with 3-phenyl isoxazoline derivatives12,13 Isoxazoline derivative with electron withdrawing group on phenyl ring underwent efficient photocycloaddition (Scheme 3.13) compared to the one without electron withdrawing group. Photocycloaddition of 4-cycano-isoxazoline 189 with furan
190 resulted in cycloaddition with the formation of azetidine 191 (Scheme 3.13).
Computational studies showed one of the major challenges for imine photocycloaddition was the rapid and competitive deactivation of excited imines chromophore compared to the rate of cycloaddition. Presence of electron withdrawing group stabilized the excited state with lower values of rate of deactivation with long lived excited imine leading cycloaddition.
O H H t-Bu O t-Bu O t-Bu N O hν O N O N + + H H 190 CN CN CN
189 191a 191b
Scheme 3.13: Photoreaction of oxazinone derivative 189 by Sampedro and co-workers.
3.2 The case for Aza Paternò-Büchi reaction
As the imine [2+2]-photocycloaddition was quite challenging, we envisioned developing novel strategies where an acyclic imine can also be added to alkene double bonds. The imine chromophore can undergo several reactions from excited state to be successful in implementing our strategy. The unwanted reaction from the excited state of imine needs to be circumvented. A possible strategy is to design a system where excitation of imine could be avoided during photoreaction with excitation of an alkene double bond that subsequently adds to the ground 179 state imine leading to azetidine. Such a transformation could be labeled as Aza Paternò-Büchi reaction.
In the second chapter, we described the strategy for Transposed Paternò-Büchi reaction, where alkene double bond of an enamide chromophore could be sensitized with xanthone sensitizer that can subsequently added to a ground state carbonyl group. In similar fashion, we envisioned excited alkene to add to a ground state imine. This also has an added advantage of sidestepping the deactivation pathways of excited imine chromophore.
In order to explore this concept, we synthesized several imine substrates as shown in the chart 3.1. The imine substrates were synthesized from corresponding aldehyde 156 which were used for Paternò-Büchi reaction discussed in chapter 2. 180
O
O NH NMe2 NPh2 O O N N N N O N O N O N O N O
156a 156c 192a 192b 192c
O O
NHTs N Ph O NMe2 N N N N N N N O N O N O N O N O
192d 192e 192f 192g 192h
O O O N N O Ph N O O HN O 2 N N Ph N O N Me2N N O N N N N
193a 193b 193c 193d 193e
TsHN Me2N N O N O TIPSO O N N NH2 NH2 N HO TIPSO
193f 193g 194 195 196
Cl O N O N O N O OH O Cl O O 199 197 198 20 158
Chart 3.1: Structure of atropisomeric imines its photoproducts, substrates for photophysics and the corresponding compounds used for their synthesis. 181
Figure 3.2 shows schematic representation of our strategy for Aza Paternò-Büchi reaction where excited sensitizer (xanthone) transfers energy to the enamide 192 which then adds to imine double bond to form azetidine derivatives 193. For comparison, a similar approach for
Transposed Paternò-Büchi reaction of 156f to oxetane 157f is shown (Scheme 3.2 left).
Energy transfer Energy transfer
X N O O N N O
156f 192
X O N O N O N
157f 193
Figure 3.2: Strategy for intramolecular [2+2]-photocycloaddition of imine double bond to alkene double bond.
3.2.1 Synthesis of enamide imines for evaluating Aza Paternò-Büchi reaction
Imines 192a-h (Chart 3.1) were synthesized by condensation of corresponding aldehyde in the presence amine derivative or hydrogen chloride salt of amine derivative in which case pyridine base was used to neutralize the salt (Scheme 3.14). Two sets of imine derivatives synthesized. Atropisomeric imine 192a had electron withdrawing hydrazide group linked to imine nitrogen that stabilizes the imine chromophore towards electron transfer reactions. The 182 imines that are designed with stabilizing group such as 192a, 192e and 192f are called stabilized imines. Imines 192b and 192g (N,N -dimethyl imine), 192c (N,N -diphenyl imine), 192d
(morpholine imine) are non-stabilized imines in which the substituent at imine nitrogen are relatively less electron withdrawing in nature. Imine 192a-h were synthesized with moderate to good yield (Scheme 3.14). Imine double bond can exist as E isomer, Z isomer or mixture of E and Z isomers. E/Z ratio of imine depends on temperature. However, in the case of 192a-d which were synthesized for atropselective photoreactions, only E isomer was observed at room temperature. The E/Z imine ratio was determined by 1H-NMR spectroscopy of the synthesized imines
R-NH2, 3Å MS, R DCM, rt, 4 h N N O or N O O R-NH2.HCl, Pyridine, 3Å MS, DCM, rt, 4 h
156a 192a-h
Scheme 3.14: Synthesis of atropisomeric imines 192a-h. 183
Table 3.1: Imines 192a-d for atropselective photoreactions.
Entry Substrate 192 Isolated yield (E/Z ratio) of imine
O O 1 a : 67% (E only) HN
2 b : X = NMe2 33% (E only)
3 c : X = NPh2 53% (E only)
4 d : O N 60% (E only)
3.2.2 Determination of racemization barrier for atropisomeric imines
For efficient transfer of axial to point chirality during the course of reaction, racemization barrier of atropisomeric imine should be prevented. Bulky substituent in the substrate, which imparts axial chirality should be large enough so that racemization rate constant should be low compared to the rate of reaction. For effective chiral transfer racemization should be a slow process. i.e krac << krxn. where krac is rate constant for racemization and krxn is the rate constant for reaction.
Figure 3.3a depicts racemization and enantiomerization process for a mixtutre of atropisomer P and M. During racemization process an enantiomerically pure compound (ee
=100%) gets converted into 50:50 mixture of each enantiomers (ee =0). 184
(a)
P P P P M M k k P P race P P race M M P P M M M M
P P M M M M
(b)
P P M M
P P kenant M M P P M M
P P M M
P = P atropisomer; M = M atropisomer
Figure 3.3: Schematic representation of racemization and enantiomerization process for atropisomer.
Enantiomerization is a process where a particular optically pure compound gets converted into other isomer14 (Figure 3.3b). P → M or M → P process has same rate constant and both contributes for racemization process krac = 2kenat.
For a mixture of P and M isomer at a time ‘t’ change in the amount of isomer with respect to time due to racemization is given by,
�� = � (� − �) Equation 3.1 ��
where krac = rate contat for racemization, � = initial concentration of P atropisomer and 185
x = � − � (concentration of racemate at time t).
�� Equation 3.2 = � �� � − � After integrating,
� Equation 3.3 ln = � � � − �
� + � �� = 2� � Equation 3.4 � − �
From the slope of plot of ln (% ee) vs time, rate constant of racemization can be calculated.
� ) Half-life of racemization( / is the time required for the enantiomeric excess to reduce from 100% to 50%.
� / = or � / = ln2/� Equation 3.5
From Eyring equation free energy of racemization can be expressed as
� � � = k � ∆ /�� Equation 3.6 ℎ where k is transmission co-efficient, kB is Boltzmann constant, R is universal gas constant and T
is temperature in Kelvin and ∆� is free energy of racemization.
Free energy of racemization is given by, 186
ℎ� Equation 3.7 ∆� = −���� kT�
The rate constant for racemization of a atropisomeric enamide 192a-d was evaluated in
° MeCN at 50 C. The plot of �� � vs 1/T can be used to extract ∆� from the slope (Table 3.2).
o O N O MeCN, 50 C N N N -1 R R krac (s ) τ1/2 (days) ‡ -1 ΔG rac (kcal.mol ) 192a-d 192a-d (P)- Isomer (M)- Isomer k rac ‡ ΔG rac τ1/2
(P)-Isomer (M)-Isomer
Scheme 3.15: Schematic representation for the racemization of atropisomeric imines.
Table 3.2: Activation energy, racemization rate constant and half-life for racemization of optically pure atropisomeric imines 192a-d.a
‡ -1 -1 Entry Compound t1⁄2rac (days) DG rac (kcal.mol ) krac (s )
1 192a 1.9 26.9 4.0 ´ 10-6
2 192b 2.1 26.9 3.7 ´ 10-6
3 192c 0.8 26.3 9.9 ´ 10-6
4 192d 1.6 26.8 5.1 ´ 10-6
a Racemization kinetics was performed in MeCN at 50 °C. Values carry an error of ±5%. Racemization kinetics was followed by HPLC analysis on a chiral stationary phase. 187
The atropisomeric imine 192a-b was found to have high racemization barrier with high value for half-life for racemization. Based on this, we expected that during reaction, there will not be racemization and atropisomeric nature will be retained for chirality transfer from the excited state leading to the formation of enantioenriched Azetidines.
3.2.3 Aza Paternò-Büchi reaction of atropisomeric imines
Photoreactions of imines 192a-d were carried out in the presence of xanthone as a triplet sensitizer in acetonitrile solvent by irradiating with 350 nm light in a Rayonet reactor (Table
3.3). Photoreaction of stabilized imines were carried out with sensitizer. Reaction resulted in the formation of the corresponding azetidine photoproduct with excellent enantiomeric excess
(atropselectivity). Atropselectivity of photoproducts 193a-d with imines 192a-d were more than
96%. Thus, axial chirality to point chirality transfer strategy was successfully employed for intramolecular [2+2]-photocycloaddition involving imine and alkene double bonds.
188
Table 3.3: Atropselctive photoreaction of imines 192a-d
R R N O N hν (~350 nm) N O Xanthone, MeCN N
25 °C, 1-8 h, N2
192a-d 193a-d
Substrate (E:Z Entry Imine Photoproduct Isolated yield [%] ratio) geometry % ee
O O
O O NH HN N N O N O N 1 67
PkA-192a PkA-193a ee = 98 (E only) PkB-192a PkB-193a ee = 97
NMe2 Me N N 2 N O N O N 21 2 R2
PkA-192b PkB-193b ee = 99 (E only) PkB-192b PkA-193b ee = 99
NPh2 N Ph2N N O N O N 3 53
PkA-193c ee = 97 (E only) PkB-192c PkB-193c ee = 97
O
N O N N N O N O 4 N 70
PkA-192d PkA-193d ee = 99 (E only) PkB-192d PkB-193d ee = 96
The photoreaction was performed in acetonitrile solvent (~2.3-3.6 mM) using a Rayonet reactor equipped ~350 nm lamps at 25 °C. 30 mol% xanthone was used as the triplet sensitizer except for substrates 192b-d for which 100 mol% sensitizer was used. The ratio of E:Z isomers in the starting material were calculated from the 1H-NMR spectra of the crude reaction mixture. The ee values are obtained by HPLC analysis on a chiral stationary phase and the results are an average of 3 runs with an error of +3%. Peak-A (PkA) and Peak-B (PkB) refers to the order of HPLC elution for a given pair of enantiomers. 189
For non-stabilized imine 192b-d reaction was not efficient with 30 mol % of xanthone acting as a sensitizer. With 100 mol % of sensitizer complete consumption of imine starting material was observed with excellent atropselectivity and moderate to good isolated yield of photoproduct 193b-d (Table 3.3; entries 2-4). We believe that non-stabilized nature of imines undergoes electron transfer from the excited state that decomposes sensitizer in addition to undergoing the desired imine [2+2] cycloaddition. This decomposition manifest with a higher sensitizer loading level. Lower isolated yield of photoproduct 193c (21%) was also due to the non-stabilizing nature of imine which was found to decompose during the reaction.
In the presence of thioxanthone as sensitizer at 420 nm irradiation, reaction was unsuccessful as the triplet energy of thioxanthone was lower than that of the enamide functionality resulting no observable reactivity.
An important observation related to Aza Paternò-Büchi reaction was that even though the expected photoproduct had three stereo centers, the isolated photoproduct had only one diastereomer. This enhances the utility and novelty of the reaction. The formation of a single stereo isomer was not dependent on the E/Z geometry of the imines. Even the study with a mixture of E/Z imines resulted in a single stereo isomer (vide infra). The geometry of the product was unequivocally established by single crystal XRD that showed the azetidine hydrogen in syn- geometry (Figure 3.4). 190
N H N H H
N O
193c 193c
N H O H N O N H
193d 193d
Figure 3.4: Single crystal XRD of 193c and 193d that showing the azetidine hydrogen in syn- geometry. 191
3.2.4 Mechanistic investigations
3.2.4.1 Analysis of E/Z isomerization of atropisomeric imine 192a during photoreaction
O O
NH NH O ~ O N hν ( 350 nm) O N N N O 10 mol% xanthone N O N N O H O CDCl3, -60 °C, t (min), N2
192a 192a-E 192a-Z (E only)
Scheme 3.16: Low temperature photoreaction of 192a under xanthone sensitization.
To gain insights into the role of imine E/Z geometry, we evaluated E:Z isomerization kinetics. We performed low temperature photoreaction on 192a and monitored the E:Z ratio using 1H-NMR spectroscopy. We utilized the well resolved enamide double bond proton resonance as spectroscopic handle. To keep the conversion low, the photoreaction was performed at -60 °C in CDCl3. Initially (t = 0 min), the 192a had only E-isomer and after 5 min of irradiation, the formation of Z-isomer was observed. The ratio of E:Z isomers changed over the course of photoreaction and after 20 min, the E:Z ratio was 1:0.45. This result clearly established that the E:Z isomerization was occurring efficiently under the photoreaction conditions. 192
20 min (E:Z = 1:0.45)
15 min (E:Z = 1:0.36)
10 min (E:Z = 1:0.29)
5 min (E:Z = 1:0.21)
0 min (E:Z = 1:0)
O Ha Hb NH O O N N N O N N O H O
192a-E 192a-Z
Figure 3.5: Low temperature 1H-NMR spectra of furoic imine derivative 192a-E and 192a-Z over the course of photoreaction (only a part of the spectra is shown for clarity). Proton resonance of Ha (for 192a-E) and Hb (for 192a-Z) was monitored over the course of photoreaction.
A similar study was carried out on lactam imine 192h which lacked the enamide chromophore (Scheme 1.17). Sensitized irradiation of 192h at room temperature resulted no observable E/Z isomerization of the imine double bond (Scheme 3.17) This lack of isomerization indicated that the enamide chromophore plays an integral role in the isomerization process 193
(Scheme 3.17). If indeed the imine is excited, one would expect E/Z isomerization upon sensitization.
O
N N hν (~350 nm) N O 10 mol% xanthone No E/Z isomerization CDCl3, rt
192h
Scheme 3.17: Room temperature photoreaction of 192h under xanthone sensitization.
We employed benzyloxy imine 192e for the photoreaction at low temperatures to monitor the change in E/Z ratio and to identify which of the isomer (E/Z isomer) is more reactive under our experimental conditions (Scheme 3.18). Unlike substrate 192a which had only E isomer before irradiation, 192e had a mixture of E and Z isomer with E:Z ratio of 1:0.3 at -60 °C.
Irradiation was performed at low temperature to maintain the low conversions of starting material and to monitor the isomerization process at early reaction times. Reaction was carried out by irradiating under ~ 350 nm light in a Rayonet reactor with 10 mol% xanthone sensitizer in
1 CDCl3 solvent (Scheme 1.18). H-NMR spectroscopic analysis of crude reaction mixture after 5 and 15 min. of irradiation showed that the E/Z ratio gradually varied with time. From initial E/Z ratio of 1:0.3, it varied to 1:0.36 and 1:0.38 at 5 min. and 15 min. respectively. As the ratio of Z increases with time on irradiation it implied that E isomer was reacting faster than Z isomer under sensitized irradiation condition. 194
Ph O
N a N O hν (~350 nm) Entry time (min) % Conversion E:Z 10 mol% xanthone 192e 1) 0 - 1:0.30 CDCl , -60 °C 3 E:Z ratio 2) 5 9% 1:0.36 t (min), N2 changes fom 1:0.3 to 1:0.4 3) 15 16% 1:0.38 192e a E:Z ratio from 1H-NMR spectroscopy in CDCl3. (E:Z = 1:0.3)
Scheme 3.18: Low temperature photoreaction of 192e under xanthone sensitization.
The results of low temperature and room temperature NMR experiments described above, can be summarized as bellow.
(a) During the photoreaction, imine double bond undergoes E/Z isomerization
(Scheme3.16).
(b) For the isomerization to happen, there is a need of enamide chromophore in the
substrate (Scheme3.17).
(c) For substrates with mixture of imines, E imine reacted faster than the corresponding Z
isomer (Scheme3.18).
3.2.4.2 Photophysical experiments
To get further insight into the reaction mechanism we performed laser flash photolysis to determine the quenching rate constant for the quenching of xanthone triplets by imines. Flash photolysis was performed with λex = 355 nm and 7 ns pulse width. Triplet lifetime was determined from triplet absorption decay monitored at 620 nm with varying quencher concentration in argon saturated acetonitrile solution. 195
Quenching the triplet of xanthone with furoichydrazide imine 192a
9 -1 -1 9 -1 -1 (kq = 7.6 ± 0.2 × 10 M S ), N,N-diphenyl imine 192c (kq = 8.5 ± 0.2 × 10 M S ) and
9 -1 -1 morpholine imine 192d (kq = 5.2 ± 0.2 × 10 M S ) was very efficient with a rate constant close to that of diffusion. This showed that excited xanthone transfers the triplet energy very efficiently to the imines 192a, 192c, and 192d. The quenching rate constant was also of the same order for the quenching of xanthone triplets by enamide 158 (3.8 ± 0.2 × 109 M-1S-1) which does not have an imine chromophore. This implied that for the quenching of xanthone triplet, imine chromophore is not necessary. In other words, excited xanthone can efficiently transfer the triplet energy to the enamide chromophore in imine substrates (e.g. 192a-d).
However, even with the substrate 192h which is lacking enamide chromophore, effective
9 -1 -1 quenching of xanthone triplet state was observed with a kq of 3.9 ± 0.2 × 10 M S . We believe that the quenching with 192h was due to the electron transfer from the tertiary nitrogen linked to imine nitrogen. Hence, this quenching was not because of energy transfer from excited sensitizer to imine double bond of 192h. If the excited sensitizer does transfer the energy to imine double bond, then it was expected that on irradiation of 192h in the presence of sensitizer at ~ 350 nm light, it should result in E/Z isomerization which is a common reaction pathway for excited imine. But such isomerization reaction was not observed in 192h (Scheme 3.17) indicating that imine was not excited during photoreaction.
When the substrate 196 which lacks both the enamide and imine chromophores, the quenching of xanthone triplet excited state was two order lower in magnitude. This indicated that for the quenching of xanthone triplets both the enamide chromophore (quenching by energy transfer) and imine chromophore (quenching by electron transfer) are required. 196
Rate constant of quenching of xanthone triplet with imine 192a (substrate with both imine and enamide chromophore) was equal almost twice the rate constant of quenching with
158 and 192h as it has both the chromophore. So, both imine and enamide chromophore likely acted independently to quench the excited triplet state of xanthone.
O O O O NH N NPh2 N TIPSO N N N N O N O N O N O N O N N O
192a 192c 192d 192h 158 196
192a 192h 6 192c
5 158
) 192a 9 -1 -1
-1 kq = (7.6±0.2) x 10 M s
s 192d 192c 9 -1 -1 6 4 kq = (8.5±0.2) x 10 M s
6 192d 9 -1 -1 kq = (5.2±0.2) x 10 M s (10 x10
3T 192h 9 -1 -1 kq = (3.9±0.2) x 10 M s
1/τ 158 9 -1 -1 k = (3.8±0.2) x 10 M s 2 q 196 7 -1 -1 kq = (5.0±0.3) x 10 M s 1 196 0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 [quencher]x10-3 (mM)
Figure 3.6: Determination of bimolecular quenching constant kq for the quenching of xanthone triplet with various with imine 192a, 192c, 192d, 192h, enamide 158 and lactam 196. 197
To summarize the results from photophysical experiments, it was clear that
(a) Xanthone was an efficient triplet sensitizer for Aza Paternò-Büchi reaction of imine
double bond with enamide double bond.
(b) Triplet excited state of xanthone was quenched by imine functionality by electron
transfer.
(c) Enamide functionality quenched the triplet of xanthone by energy transfer.
(c) Lack of imine and enamide chromophore resulted in inefficient quenching of the
xanthone triplet state.
3.2.4.3 XRD data for Aza Paternò-Büchi photoproducts 193c and 193f
Single crystal XRD analysis of the photoproduct 193c was formed from N-N diphenyl derivative 192c that was formed which had only E isomer and the photoproduct 193f that was formed from 192f which had a mixture of E and Z isomer with E:Z ratio of 1:5.5 led to single diastereomeric product.
Irrespective of the starting imine geometry i.e, starting material which was a single isomer (only E) or mixture of isomers (E and Z), the XRD structure showed that only one type of stereoisomeric product was formed where the azetidine ring hydrogen are in syn orientation. 198
N O H S N NH O H H H N H H N O N O
193c 193f
Figure 3.7: XRD structure of photoproduct 193d and 193f
If the imine geometry would have had any role in the nature of product formed, one would expect that E form and Z form of isomer of imine should lead to two different types of stereoisomeric photoproducts. But as we observed a single stereoisomeric product, this indicated that the E/Z ratio of imine does not have any role in product formation. It also suggested an involvement of a common intermediated in the reaction pathway. 199
3.2.5 Mechanistic rational for Aza Paternò-Buüchi reaction
Based on control experiments described above, photophysical experiments and XRD data the plausible mechanism for Aza Paternò-Büchi reaction is detailed in Figure 3.8.
R1
1 N O N O R N k1 N
k-1
Z-192 X hν 3[X]* E-192
3[Z] * 3[E]* X = Xanthone kr(Z) kr(E) H H R1 N N O O 1 N N E-192 E-192 R H H and H H and Z-192 ISC ring ring ISC Z-192 opening opening TBR-192Z TBR-192E ISC ISC ISC = intersystem crossing H H H R1 1 N N O R H N 1 N N O R H N O H H H H ring pyramidal closure inversion & ring SBR-192Z SBR-192E 193 closure
Figure 3.8: Proposed Mechanism for Aza Paternò-Büchi reaction
At room temperature imine can have mixture of E and Z isomers or only E or Z isomer depending on the electronic nature of the imine substituent. Both E and Z isomers can be in equilibrium with each other and the E/Z ratio can be controlled by temperature. On photoexcitation of xanthone, triplet energy transfer from sensitizer generates the triplet excited state of the enamide. This triplet excited enamide undergoes stepwise cyclization leading to 200 biradical biradical TBR-192Z and TBR-192E that can be interconverted by a C - N bond rotation. The C - C bond formed in the first step results in a 1,4-biradical centered on the nitrogen. This diradical can revert to the starting material, scrambling the E/Z geometry.
Therefore, even if the triplet biradical was formed from only E or only Z isomer, the reversal of
1,4-biraical results in the formation of mixture of E and Z imine 192E and 192Z respectively.
This step was supported by the control experiment in Scheme 3.16 where pure E isomer 192a upon sensitization resulted in the formation of mixture of E and Z isomer. In addition, the presence of enamide functionality was necessary to observe E/Z imines isomerization (Scheme
3.17; substrate 192h)
The triplet biradical TBR-192Z and TBR-192E can undergo intersystem cross to form singlet biradical SBR-192Z and SBR-192E that can cyclize to form the azetidine product 193. In addition singlet biradical SBR-192E can also result in the formation of final product 193 by pyramidal inversion. This explanation was derived from the XRD structure of photoproduct 193c and 193f which are formed from imine 192c (only E isomer) and 192f (mixture of E and Z isomer). So irrespective of whether the imine consist of a E/Z mixture or a single isomer (either only E or only Z isomer) the final product formed will be a single stereoisomeric product with syn orientation of the hydrogen in the four-membered ring.
3.3 Summary
For the first time, we have successfully developed the cycloaddition of C=C double bond to C=N double bond by utilizing excitation of an alkene bond and adding to an imine functionality. The reaction is tolerant to both stabilized and non-stabilized imines. The strategy provided is simple and straightforward access to azetidine that are relevant for the pharmaceutical industry and in material chemistry.15 201
3.4 Experimental section
3.4.1 General methods
All commercially obtained reagents/solvents were used as received; chemicals were purchased from Alfa Aesar®, Sigma-Aldrich®, Acros organics®, TCI America®, Mallinckrodt®, and Oakwood® Products, and were used as received without further purification. Unless stated otherwise, reactions were conducted in oven-dried glassware under nitrogen atmosphere. 1H-
NMR and 13C-NMR spectra were recorded on Varian 400 MHz (100 MHz for 13C) and on 500
MHz (125 MHz for 13C) spectrometers. Data from the 1H-NMR spectroscopy are reported as chemical shift (δ ppm) with the corresponding integration values. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s
(singlet), b (broad), d (doublet), t (triplet), q (quartet), m (multiplet) and virt (virtual). Data for
13C NMR spectra are reported in terms of chemical shift (δ ppm). High-resolution mass spectrum data in Electrospray Ionization mode were recorded on a Bruker – Daltronics® BioTof mass spectrometer in positive (ESI+) ion mode. HPLC analyses were performed on Waters® HPLC equipped with 2525 pump or on Dionex® Ultimate 3000 HPLC. Waters® 2767 sample manager was used for automated sample injection on Waters® HPLC or Ultimate 3000 sample injector was used for injection on Dionex® HPLC. All HPLC injections on Waters® HPLC were monitored using a Waters® 2487 dual wavelength absorbance detector at 254 and 270 nm or on
Dionex®. HPLC were monitored using a diode array detector (DAD3000125). Analytical and semi-preparative injections were performed on chiral stationary phase using various columns as indicated below 202 i) Regis® PIRKLE COVALENT (R,R) WHELK–01
a) 25 cm ´ 4.6 mm column for analytical injections
b) 25 cm ´ 10 mm column for semi-preparative injections ii) CHIRACEL® OD-H
a) 0.46 cm ´ 25 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections iii) CHIRALPACK® IC
a) 0.46 cm ´ 25 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections iv) CHIRALPAK® AD-H
a) 0.46 cm ´ 15 cm column for analytical injections
b) 10 mm ´ 25 cm column for semi-preparative injections
Masslynx software version 4.1 was used to monitor/analyze the HPLC injections and to process HPLC traces. Igor Pro® Software version 6.0 was used to process the HPLC graphics.
Absorbance measurements were performed using Agilent technologies® Cary 300 UV-Vis spectrophotometer using UV quality fluorimeter cells (with range until 190 nm) purchased from
Luzchem. When necessary, the compounds were purified by combiflash equipped with dual wavelength UV-Vis absorbance detector (Teledyn ISCO) using hexanes:ethyl acetate as the mobile phase and Redisep® cartridge filled with silica (Teledyne ISCO) as stationary phase. In 203 some cases, compounds were purified by column chromatography on silica gel (Sorbent
Technologies®, silica gel standard grade: porosity 60 Å, particle size: 230 x 400 mesh, surface area: 500 – 600 m2/g, bulk density: 0.4 g/mL, pH range: 6.5 – 7.5). Unless indicated, the
Retardation Factor (Rf) values were recorded using a 5-50% hexanes:ethyl acetate as mobile
® phase and on Sorbent Technologies , silica Gel TLC plates (200 mm thickness w/UV254).
Photophysical Methods.
Spectrophotometric solvents (Sigma-Aldrich®) were used when ever necessary unless or otherwise mentioned. UV quality fluorimeter cells (with range until 190 nm) were purchased from Luzchem®. Absorbance measurements were performed using a Shimadzu® UV-2501PC
UV-Vis spectrophotometer. Emission spectra were recorded on a Horiba Scientific® Fluorolog 3 spectrometer (FL3-22) equipped with double-grating monochromators, dual lamp housing containing a 450-watt CW xenon lamp and a UV xenon flash lamp (FL-1040),
Fluorohub/MCA/MCS electronics and R928 PMT detector. Emission and excitation spectra were corrected in all the cases for source intensity (lamp and grating) and emission spectral response
(detector and grating) by standard instrument correction provided in the instrument software.
Fluorescence (steady state) and phosphorescence (77 K) emission spectra were processed by
FluorEssence® software. Phosphorescence lifetime measurements were performed using DAS6®
V6.4 software. The goodness-of-fit was assessed by minimizing the reduced chi squared function and further judged by the symmetrical distribution of the residuals.
204
3.4.2 Synthetic protocol for lactam aldehyde 198
The lactam aldehyde 198 and its precursors were synthesized according to procedures reported in the literature.
Cl 1. Et3N, EtOAC, NH2 0 °C to 25 °C, 4 h O N OTIPS OTIPS Cl 2. 6% NaOH/IPA, 5 h, rt O 195 199 196
DMP, DCM TBAF, THF O N 0 to 25 °C, 2 h O N OH O reflux, 2 h
197 198
Scheme 3.19: Scheme for the synthesis of lactam aldehyde 198.
3.4.3 Procedure for the synthesis of lactam imines and their precursors
3.4.3.1 Synthesis of 1-(2-(2-((triisopropylsilyl)oxy)ethyl)phenyl)pyrrolidin-2-one 196
Cl NH2 O 1. Et3N, EtOAC, N 0 °C - rt, 4 h Cl OTIPS 2. 6% NaOH/IPA, 5 h, rt OTIPS O 195 199 196
Scheme 3.20: Synthesis of TIPS pyrrolidinone derivative 196.
The aniline derivative 195 was synthesized according to a procedure reported in the literature. To a solution of TIPS protected aniline derivative 195 (6 g, 20.4 mmol, 1.0 equiv.) in ethyl acetate (50 mL) at 0 °C, triethylamine (3.3 mL, 23.6 mmol, 1.1 equiv.) and
4-chlorobutyrylchloride 199 (2.4 mL, 21.4 mmol, 1.05 equiv.) was added. The mixture was 205 allowed to warm to room temperature over 4 h. After the reaction, the mixture was quenched with DI water and extracted with EtOAc (3 x 30 mL) and brine solution (20 mL). The organic layer was dried over anhyd. Na2SO4 and the solvent was removed under reduced pressure. The residue obtained was dissolved in 1:1 mixture of 6% NaOH/IPA (90 mL). The mixture was stirred at room temperature for 5 h. After the reaction, the mixture was extracted with EtOAc (3 x 30 mL). The organic layer was dried over anhyd. Na2SO4 and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by combiflash using hexanes: ethyl acetate mixture (90:10).
Rf = 0.35 (90% hexanes: 10% ethyl acetate), Yield = 81%.
206
1 H-NMR (500 MHz, CDCl3, δ ppm): 7.35-7.33 (m, 1H), 7.24-7.22 (m, 2H), 7.11-7.09 (m, 1H),
3.87-3.84 (t, J = 9 Hz, 2H), 3.73-3.69 (t, J = 8.5 Hz 2H), 2.80-2.77 (t, J = 9 Hz, 2H), 2.57-2.53 (t,
J = 10.5 Hz, 2H), 2.23-2.14 (m, 2H) and 1.01 (s, 21H). OTIPS N O
Figure 3.9 : 1H-NMR spectra of lactam derivative 196. 207
13 C-NMR (100 MHz, CDCl3, δ ppm): 175.1, 137.9, 137.0, 131.1, 128.2, 127.6, 127.3, 64.0, 51.8,
35.2, 31.5, 19.2, 18.2 and 12.2.
* OTIPS N O
Figure 3.10: 13 C-NMR spectra lactam derivative 196. 208
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 384.2335
Observed : 384.2341
|Dm| : 1.5 ppm
O N OTIPS
Figure 3.11: HRMS of lactam derivative 196.
209
3.4.3.2 Synthesis of 1-(2-(2-hydroxyethyl)phenyl)pyrrolidin-2-one 197
O N TBAF, THF O N reflux, 2 h OTIPS OH 196 197
Scheme 3.21: Synthesis of hydroxyethylpyrolidinone derivative 197
To a solution of 196 (6.3 g, 17.4 mmol, 1.0 equiv.) in THF (30 mL) under N2 atmosphere and at room temperature, TBAF (1M in THF, 1.1 equiv.) was added. The resulting solution was heated to reflux and maintained until complete consumption of starting material. After the reaction, the mixture was cooled to room temperature, diluted with DI water (30 mL) and extracted with ethyl acetate (2 ´ 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhyd. Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using a DCM:MeOH (95:5) mixtures.
Rf = 0.30(5% Methanol: 95% Dichloromethane), Yield = 60%.
210
1 H-NMR (500 MHz, CDCl3, δ ppm): 7.39-7.38 (m, 1H), 7.35-7.28 (m, 2H), 7.16-7.15 (m, 1H),
3.90-3.88 (t, J = 6.5 Hz, 2H), 3.79-3.76 (t, J = 7.0 Hz, 2H), 2.82-2.79 (t, J = 6.5 Hz, 2H), 2.73
(bs, 1H), 2.63-2.60 (t, J = 8.0 Hz, 2H) and 2.29-2.23 (m, 2H).
* OH N O
Figure 3.12: 1H-NMR spectra of lactam alcohol derivative 197. 211
13 C-NMR (100 MHz, CDCl3, δ ppm): 175.8, 137.8, 137.2, 130.8, 128.4, 127.6, 127.3, 62.5, 51.9,
34.5, 31.5 and 19.1.
* OH N O
Figure 3.13: 13C-NMR spectra of lactam alcohol derivative 197. 212
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 228.1001
Observed : 228.1012
|Dm| : 4.8 ppm
O N OH
Figure 3.14: HRMS of lactam alcohol derivative 197. 213
3.4.3.3 Synthesis of 2-(2-(2-oxopyrrolidin-1-yl)phenyl)acetaldehyde 198
DMP, DCM O N 0 °C - rt, 2 h O N O
OH 197 198
Scheme 3.22: Synthesis of pyrrolidinyl aldehyde derivative 198.
To a slurry of Dess-Martin periodinane (DMP) (2.1 g, 4.9 mmol, 1.2 equiv) in DCM (15 mL) at 0 oC, a solution of corresponding alcohol derivative 197 (970 mg, 4.1 mmol, 1.0 equiv) in
DCM (5 mL) was added and the resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with water (10 mL) and the mixture was extracted with DCM
(2 ´ 15 mL). The combined organic layer was dried over anhyd. Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using a DCM:MeOH (95:5) mixtures to get the title product.
Rf = 0.30 (5% Methanol: 95% Dichloromethane), Yield = 81%
214
1 H-NMR (400 MHz, CDCl3, δ ppm): 9.58-9.57 (t, J = 1.6 Hz, 1H), 7.26-7.12 (m, 4H), 3.65-3.62
(t, J = 6.8 Hz, 2H), 3.58-3.576 (d, J = 2.0 Hz, 2H), 2.44-2.40 (t, J = 16 Hz, 2H), 2.10-2.03 (q, J =
7.2 Hz, 2H). O H O N
Figure 3.15: 1H-NMR spectra of pyrrolidinyl aldehyde derivative 198. 215
13 C-NMR (100 MHz, CDCl3, δ ppm): 199.5, 174.3, 138.4, 131.8, 130.7, 128.8, 128.3, 126.4,
51.1, 47.4, 31.4 and 19.1.
O O * N
Figure 3.16: 13 C-NMR spectra of pyrrolidinyl aldehyde derivative 198. 216
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 226.0844
Observed : 226.0850
|Dm| : 2.7 ppm
O N O
Figure 3.17: HRMS of pyrrolidinyl aldehyde derivative 198.
217
Rf = 0.30 (80% hexanes: 20% ethyl acetate), Yield =86%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.38-7.34 (m, 4H), 7.14-7.09 (m, 6H), 6.98 (s, 1H), 6.93 (s,
1H), 6.52-6.50 (m, 1H), 6.23 (d, J = 4.9 Hz, 1H), 5.46 (d, J = 4.9 Hz, 1H), 3.58-3.47 (m, 2H),
2.31 (s, 3H), 2.13 (s, 3H), 1.31 (s, 3H) and 1.27 (s, 3H). O N Ph N N Ph
Figure 3.18: 1H-NMR spectra of diphenylimine derivative 192c. 218
13 C-NMR (100 MHz, CDCl3, δ ppm): 181.8, 144.2, 138.7, 136.99, 136.8, 136.6, 132.2, 131.6,
130.4, 129.95, 129.1, 124.3, 122.6, 117.9, 46.2, 35.9, 23.96, 23.4, 21.4 and 18.1. O N Ph N N Ph
Figure 3.19: 13 C-NMR spectra for diphenylimine derivative 192c. 219
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 446.2208
Observed : 446.2218
|Dm| : 2.2 ppm
N O N Ph N Ph
Figure 3.20: HRMS of diphenylimine derivative 192c.
220
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK-IC
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 90:10
Flow rate : 1.0 mL/min
Retention times (min) : ~ 11.5 [(A)-192c] and ~ 13.8 [(B)-192c]
For preparative conditions,
I). Column : CHIRALPAK-IC
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 90:10
Flow rate : 3.0 mL/min
Retention times (min) : ~ 28 [(A)-192c] and ~ 36.3 [(B)-192c]
(A and B refers to the order of elution for a given pair of isomers on HPLC)
221
Rf = 0.70 (50% hexanes: 50% ethyl acetate), Yield = 43%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.24 (t, J = 6.0 Hz, 1H, minor), 7.32-7.25 (m, 5H, major+minor), 6.97-6.96 (m, 1H, major+minor), 6.89 (s, 1H, major), 6.87 (s, 1H, minor), 6.67 (t,
J = 4.8 Hz, 1H, major), 6.23 (d, J = 5.2 Hz, 1H, major), 6.20 (d, J = 4.8 Hz, 1H, minor), 5.43 (m,
1H, major+minor), 5.08 (s, 2H, major), 5.03 (s, 2H, minor), 3.61-3.26 (m, 2H, major+minor),
2.27 (s, 3H, major+minor), 2.09 (s, 3H, major+minor), 1.28 (s, 3H, minor), 1.27 (s, 3H, minor),
1.26 (s, 3H, major) and 1.21 (s, 3H, major). O N Bn N O
Figure 3.21: 1H-NMR spectra of benzyloxy imine derivative192e. 222
13 C-NMR (100 MHz, CDCl3, δ ppm):181.89, 181.87, 149.8, 149.3, 138.9, 138.8, 138.1, 137.9,
136.96, 136.85, 135.6, 134.9, 132.1, 132.0, 131.4, 131.1, 130.7, 130.6, 128.99, 128.86, 128.8,
128.6, 128.4, 128.3, 128.0, 118.3, 118.1, 76.1,75.8, 46.2, 32.1, 29.3, 23.83, 23.6, 23.5, 21.3, 18.1 and 18.0.
* O N Bn N O
* = solvent
Figure 3.22: 13 C-NMR spectra of benzyloxy imine derivative192e. 223
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 385.1892
Observed : 385.1899
|Dm| : 1.8 ppm Bn O N O N
Figure 3.23: HRMS of benzyloxy imine derivative 192e. 224
3.4.4 Racemization kinetics for non-biaryl atropisomeric imines
Racemization kinetics of optically pure atropisomeric imine derivatives 192 were carried out at 50 oC in acetonitrile solvent. The racemization rate was followed by HPLC analyses on a chiral stationary phase at different time intervals (Scheme 3.15). The activation energy (Table
3.2 ) for racemization was computed from equations 1 and 2.
4.60 4.60 192a 192b 4.58 4.58
4.56 4.56
ln (%ee)
ln (%ee)
4.54 4.54
0.00 0.05 0.10 0.15 0.20 0.00 0.05 0.10 0.15 0.20 Time (days) Time (days)
4.60 192c 4.60 192d 4.55 4.58 4.56 4.50
ln (%ee)
ln(%ee) 4.54 4.45 4.52
0.00 0.05 0.10 0.15 0.20 0.00 0.05 0.10 0.15 0.20 Time (days) Time (days)
Figure 3.24: Racemization kinetics of atropisomeric imines 192 in acetonitrile at 50 ºC. 225
3.4.5 Photophysical studies of imine derivatives
O O O
O NH NPh2 N N N N N N N O N O N O N O
192a 192c 192d 192h
TIPSO N O N O O
O
158 196 20 (Sensitizer)
Chart 3.2: Substrates and sensitizer employed for photophysical studies.
Bimolecular quenching rate constants of xanthone triplets were determined by laser flash photolysis. Acetonitrile solutions of xanthone were prepared such that the absorption at the excitation wavelength (355 nm) was 0.3 (1 cm path length). To these solutions appropriate amounts of enamides 192 were added. The solutions was deoxygenated by purging argon.
Absorbance decay traces were recorded at 620 nm (sensitizer triplet absorption) and fitted to a mono-exponential function. The resulting observed triplet lifetimes (tT) were plotted against the enamide concentration. The bimolecular quenching rate constants (kq) were obtained from the slope of these plots and are summarized in Table 3.4. 226
1.0
0.9 )
-1 0.8
s TIPSO
6 O 6 N 0.7 x10 (10 T
1/ τ 0.6
0.5 196 k 1q = (5.0±0.3) x 107 M-1s-1 0.4 q 0 2 4 6 8 10 x10-3 [quencher] (mM)
Figure 3.25: Determination of the bimolecular quenching rate constant kq of quenching of xanthone triplet states by 196 using laser flash photolysis (λex = 355 nm, 7 ns pulse width).
Inverse triplet lifetime determined from triplet absorption decay traces monitored at 620 nm with varying concentration of 196 in argon saturated acetonitrile solutions.
Table 3.4: Bimolecular quenching rate constant (kq) for the quenching of xanthone triplet states by substrates
-1 -1 Entry Imines kq (M s ) 1 192a 7.6±0.2 ´ 109 2 192c 8.5±0.2 ´ 109 3 192d 5.2±0.2 ´ 109 4 192h 3.9±0.2 ´ 109 5 158 3.8±0.2 ´ 109 6 196 5.0±0.3 ´ 107 227
3.4.6 General irradiation procedure and characterization of imine derivatives
3.4.6.1 General irradiation procedure for the imine derivatives 192a-d,192g
1 R R1 O hν ∼350 nm N N O N Xanthone, MeCN N R2 R2 25 °C, 1-8 h, N2
R2 R2 192a-d, 192g 193a-d, 193g (E:Z mixture)
Scheme 3.23: General irradiation procedures for imine derivatives 192a-d, 192g
A N2 saturated solution of imine derivatives 192a-d, 192g in MeCN (1mg/1mL or 2.5-4.1 mM) with xanthone sensitizer (30 mol% for 192a and 192b-d, 192g 100 mol% of xanthone was employed) was irradiated in a Rayonet reactor equipped with ~350 nm bulbs until the reaction was complete as monitored by the 1H-NMR spectroscopy (and TLC). After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by
Combiflash to get the pure product.
The large-scale photoreactions were performed as batches on the same concentration (8 ×
10 mL test tubes per batch) using merry-go-round apparatus. After the reaction, the solvent was evaporated under reduced pressure and the residue was purified by combiflash to get the pure product.
Note: For the given scale (10 mg) the reaction was completed in 1-8 h. Longer irradiation leads to decomposition of photoproducts. The Rf of most of the photoproducts and their starting materials were similar, so 1H-NMR spectroscopy was used simultaneously to monitor the 228 reaction progress. A solution of imines undergoes decomposition even when stored in dark, so the operations have to be carried out so as to reduce the pre-irradiation time to the least time possible.
Rf = 0.40 (50% hexanes: 50% ethyl acetate), Yield = 67%.
229
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.87 (s, 1H), 7.47-7.44 (m, 1H), 7.16-7.15 (m, 1H), 6.92 (s,
1H), 6.75 (s, 1H), 6.51 (s, 1H), 5.15-5.12 (m, 1H), 4.90-4.87 (m, 1H), 4.16-4.13 (m, 1H), 2.99-
2.91 (m, 1H), 2.78-2.74 (m, 1H), 2.25 (s, 6H), 1.21 (s, 3H) and 1.18 (s, 3H). O NH O N N O
Figure 3.26: 1H-NMR of spectra furoic hydrazide photoproduct 193a. 230
13 C-NMR (100 MHz, CDCl3, δ ppm): 178.95, 158.95, 147.1, 144.6, 136.3, 134.6, 132.4, 132.3,
129.5, 127.2, 115.4, 112.4, 72.0, 64.4, 49.1, 45.4, 32.4, 22.8, 21.2, 18.1 and 17.5. O NH O N N O
Figure 3.27: 13 C-NMR spectra of furoic hydrazide photoproduct193a. 231
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 388.1637
Observed : 388.1637
|Dm| : 0.0 ppm
O H N N O N O
Figure 3.28: HRMS for furoic hydrazide photoproduct 193a. 232
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK-ADH
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 90:10
Flow rate : 1.0 mL/min
Retention times (min) : ~ 17.9 [(A)-193a] and ~ 60.9 [(B)-193a]
233
1 H-NMR (400 MHz, CDCl3, δ ppm): 6.90 (s, 1H), 6.72 (s, 1H), 4.15-4.11 (m, 1H), 3.87-3.84 (t,
J = 5.8 Hz, 1H), 3.74-3.73 (d, J = 5.6 Hz, 1H), 3.01-2.95 (dd, J = 16.8, 8.4 Hz, 1H), 2.77-2.72
(m, 1H), 2.41 (s, 6H), 2.24 (s, 3H), 2.22 (s, 3H), 1.21 (s, 3H) and 1.17 (s, 3H). N N N O *
Figure 3.29: 1H-NMR spectra for N,N-dimethylhydrazine photoproduct 193b. 234
13 C-NMR (100 MHz, CDCl3, δ ppm): 178.98, 136.80, 131.50, 128.14, 67.97, 57.80, 48.30,
45.04, 42.60, 34.30, 29.90, 23.26, 21.17, 18.07 and 18.03. * N N N O
Figure 3.30: 13C NMR spectra for N,N-dimethylhydrazine photoproduct 193b. 235
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 322.1895
Observed : 322.1898
|Dm| : 0.9 ppm
N N O N
Figure 3.31: HRMS spectra for N,N-dimethylhydrazine photoproduct 193b.
236
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK-ADH
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 90:10
Flow rate : 1.0 mL/min
Retention times (min) : ~ 12.55 [(A)-193b] and ~ 45.35 [(B)-193b] 237
Rf = 0.30 (80% hexanes: 20% ethyl acetate), Yield = 53%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.32-7.28 (m, 4H), 7.07-6.95 (m, 7H), 6.74 (s, 1H), 4.02-
3.98 (m, 1H), 3.84-3.82 (m, 1H), 3.74-3.71 (m, 1H), 3.13-3.08 (m, 1H), 2.94-2.89 (dd, J = 17.9,
8.1 Hz, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 1.24 (s, 4H), 1.16 (s, 3H). Ph Ph N N N O
Figure 3.32: 1H-NMR spectra for N,N-diphenylhydrazine photoproduct 193c. 238
13 C-NMR (100 MHz, CDCl3, δ ppm): 179.2, 144.8, 136.1, 134.6, 132.0, 131.7, 129.6, 127.5,
123.5, 122.5, 72.2, 62.9, 47.9, 45.3, 30.8, 29.9, 22.8, 21.2, 18.4 and 18.0. Ph Ph N N N O
Figure 3.33: 13C-NMR spectra for N,N-diphenylhydrazine photoproduct 193c. 239
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 388.1637
Observed : 388.1641
|Dm| : 1.0 ppm
Ph N Ph N N O
Figure 3.34: HRMS for N,N-diphenylhydrazine photoproduct 193c. 240
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK-IC
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 90:10
Flow rate : 1.0 mL/min
Retention times (min) : ~ 10.2 [(A)-193c] and ~ 14.04 [(B)-193c] 241
Rf = 0.22 (50% hexanes: 50% ethyl acetate), Yield = 37%.
1 H-NMR (500 MHz, CDCl3, δ ppm): 6.95 (s, 1H), 6.78 (s, 1H), 4.28-4.24 (m, 1H), 3.93-3.88 (m,
2H), 3.77-3.74 (m, 4H), 3.06-3.01 (m, 1H), 2.81-2.71 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 1.25 (s,
3H) and 1.22 (s, 3H). O N N N O
Figure 3.35: 1H-NMR spectra for morpholinehydrazine photoproduct193d. 242
13 C-NMR (100 MHz, CDCl3, δ ppm): 178.96, 136.3, 134.6, 133.0, 132.5, 129.4, 127.1, 67.7,
67.4, 58.3, 51.96, 48.5, 45.1, 34.2, 23.2, 21.23, 21.22, 18.22 and18.15. O N N N O
Figure 3.36: 13C-NMR spectra for morpholinimine photoproduct193d. 243
HRMS-ESI (m/z) ([M + Na]+):
Calculated : 342.2181
Observed : 342.2187
|Dm| : 1.7 ppm
O
N N O N
Figure 3.37: HRMS for morpholinimine photoproduct 193d.
244
HPLC analysis conditions:
For analytical conditions,
I). Column : CHIRALPAK-IC
Abs. detector wavelength : 254 nm and 270 nm
Mobile phase : Hexanes:2-propanol = 80:20
Flow rate : 1.0 mL/min
Retention times (min) : ~ 23 [(A)-193d] and ~ 37 [(B)-193d] 245
Rf = 0.10 (50% hexanes: 50% ethyl acetate), Yield = 33%.
1 H-NMR (400 MHz, CDCl3, δ ppm): 7.43-7.41 (m, 1H), 7.23-7.22 (m, 1H), 7.09-7.08 (m, 2H),
4.16 (m, 1H), 3.90-3.88 (m, 1H), 3.78 (s, 1H), 3.07-3.00 (m, 1H), 2.78-2.74 (m, 1H), 2.42 (s, 6H),
1.20 (s, 3H) and 1.16 (s, 3H). O N N N
Figure 3.38: 1H-NMR spectra for 193g. 246
13C-NMR (100 MHz, CDCl3, δ ppm): 179.6, 135.5, 131.5, 129.1, 126.7, 125.8, 125.4, 68.4, 57.3,
47.3, 44.8, 42.6, 32.3, 22.9 and 18.6. O N N N
Figure 3.39: 13C-NMR of 193g. 247
3.4.7 UV-Visible absorption spectra
0.8 0.6
192a (~0.02 mM) 0.5 0.6 193a (~0.02 mM) 192b (~0.02 mM) 0.4 193b (~0.02 mM) 0.4 0.3
Absorbance 0.2
Absorbance 0.2 0.1
0.0 0.0 220 240 260 280 300 320 340 360 200 220 240 260 280 300 320 340 360 Wavelength (nm) Wavelength (nm)
Figure 3.40: UV-Vis absorption spectra.
3.4.8 X-ray structural parameters
Single crystal X-ray diffraction data of the compounds 193c-d, and 193f were collected on a Bruker Apex Duo diffractometer with a Apex 2 CCD area detector at T = 100K. Cu radiation was used. All structures were processed with Apex 2 v2011.4-1 software package
(SAINT v. 7.68A, XSHELL v. 6.14). Direct method was used to solve the structures after multi- scan absorption corrections. Details of data collection and refinement are given in the Table 3.5 below. 248
Table 3.5: X-ray structural parameters of 193c-d, and 193f Entry 193c 193d 193f
Formula C21H23N3O3S C28H29N3O C20H27N3O2
FW 397.48 423.54 341.45
cryst. size_ma [mm] 0.24 0.21 0.375
cryst. size_mid [mm] 0.1 0.182 0.3
cryst. size_min [mm] 0.052 0.123 0.15
cryst. system Monoclinic Triclinic triclinic
Space Group, Z C2/c, 8 P-1, 2 P-1, 2
a [Å] 24.7877(6) 8.1841(6) 6.8793(3)
b [Å] 10.2096(3) 10.0931(8) 9.6110(4)
c [Å] 16.2987(4) 14.5899(11) 13.9734(6)
α [Å] 90 104.083(3) 94.4661(14)
ß [Å] 112.7980(10) 93.780(3) 96.5293(15)
γ [Å] 90 103.469(3) 96.6347(13)
V [Å3] 3802.51(17) 1127.15(15) 907.85(7)
3 ρcalc [g/cm ] 1.389 1.248 1.249
µ [cm-1] 1.747 0.077 0.648 249
CuKα (λ = CuKα (λ = Radiation Type MoKα (λ = 0.71073) 1.54178) 1.54178)
F(000) 1680.0 452.0 368.0 no of measured refl. 27306 25111 11329 no of indep. refl. 3363 4680 3149 no of refl. (I ≥ 2σ) 2292 3368 3013
Resolution [Å] 0.84 0.76 0.84
R1/wR2 (I ≥ 2σ)a [%] 3.24/7.86 4.59/9.35 4.21/10.82
R1/wR2 (all data) [%] 3.71/8.13 7.54/10.66 4.33/10.94
(a) Structure of photoproduct 193c (crystalized from hexanes/chloroform mixture).
N H N H H
N O
193c 193c 250
(b) Structure of photoproduct 193d (crystalized from hexanes/chloroform mixture).
N H O H N O N H
193d 193d
Figure 3.41: XRD structure of photoproduct (a) 193c and (b) 193d
3.5 References
(1) Padwa, Albert. Photochemistry of the Carbon-Nitrogen Double Bond. Chem. Rev. 1977, 77,
37–68.
(2) Padwa, A.; Albrecht, F. Photoisomerization about the Carbon-Nitrogen Double Bond of an
Oxime Ether. J. Am. Chem. Soc. 1972, 94, 1000–1002.
(3) Padwa, A.; Albrecht, F. Excimer Involvement in the Photoisomerization of an Oxime Ether.
Tetrahedron Lett. 1974, 15, 1083–1086.
(4) Huyser, E. S.; Wang, R. H. S.; Short, W. T. Photochemical and Peroxide Induced
Reductions of Benzophenone Imine with Secondary Alcohols. J. Org. Chem. 1968, 33,
4323–4325.
(5) Stermitz, F. R.; Seiber, R. P.; Nicodem, D. E. Imine Photoalkylations. Papaverine,
Phenanthridine, and a General Mechanism. J. Org. Chem. 1968, 33, 1136–1140. 251
(6) Stermitz, F. R.; Wei, C. C. Photochemistry of Aromatic N-Heterocycles. IV. McLafferty
Rearrangement and Type II Photocleavage Comparisons in a New System. 2-Substituted
Quinolines. J. Am. Chem. Soc. 1969, 91, 3103–3104.
(7) Howard, K. A.; Koch, T. H. Photochemical Reactivity of Keto Imino Ethers. V. (2 + 2)
Photocycloaddition to the Carbon-Nitrogen Double Bond of 3-Ethoxyisoindolone. J. Am.
Chem. Soc. 1975, 97, 7288–7298.
(8) Tsuge, O.; Tashiro, M.; Oe, K. Photochemical Reaction of 2,5-Diphenyl-1,3,4-Oxadiazole
with Indene. Tetrahedron Lett. 1968, 9, 3971–3974.
(9) Oe, K.; Tashiro, M.; Tsuge, O. Photochemistry of Heterocyclic Compounds. 5.
Photochemical Reaction of 2,5-Diaryl-1,3,4-Oxadiazoles with Indene. J. Org. Chem. 1977,
42, 1496–1499.
(10) Oe, K.; Tashiro, M.; Tsuge, O. Photochemistry of Heterocyclic Compounds. 5.
Photochemical Reaction of 2,5-Diaryl-1,3,4-Oxadiazoles with Indene. J. Org. Chem. 1977,
42, 1496–1499.
(11) Koch, T. H.; Olesen, J. A.; DeNiro, J. Unusually Weak Carbon-Carbon Single Bond. J. Am.
Chem. Soc. 1975, 97, 7285–7288.
(12) Sampedro, D.; Soldevilla, A.; Campos, P. J.; Ruiz, R.; Rodríguez, M. A. Regio- and
Stereochemistry of [2 + 2] Photocycloadditions of Imines to Alkenes: A Computational and
Experimental Study. J. Org. Chem. 2008, 73, 8331–8336.
(13) Sampedro, D. Computational Exploration of the Photocycloaddition of Imines to Alkenes.
Chem.Phys.Chem. 2006, 7, 2456–2459.
(14) Kumarasamy, E.; Kandappa, S. K.; Raghunathan, R.; Jockusch, S.; Sivaguru, J. Realizing
an Aza Paternò–Büchi Reaction. Angew. Che. Int. Ed. 2017, 56, 7056–7061. 252
(15) Gleede, T.; Reisman, L.; Rieger, E.; Mbarushimana, P. C.; Rupar, P. A.; Wurm, F. R.
Aziridines and Azetidines: Building Blocks for Polyamines by Anionic and Cationic Ring-
Opening Polymerization. Polym. Chem. 2019, 10, 3257–3283. 253
4 CHAPTER 4: ENTROPIC CONTROL OF PHOTOCHEMICAL REACTION: A
CASE STUDY INVOLVING [3+2]-PHOTOCYCLOADDITION
Introduction
Unlike thermal reaction, excited state reactions are short lived in which the environment and hence the entropic factors play a decisive role in the deactivation pathway.1-2 There are established reactions where temperature can have intrinsic effect in the product distribution. The temperature dependence of photochemical reactivity can be deciphered by Eyring parameters
(Equation 4.1). But seldom a reaction can be manipulated where increase in the temperature opens pathways leading to products. This chapter details variety of examples in which [2+2] vs
[3+2] photocycloaddition can be controlled by temperature.
4.1 Temperature effect on photochemical reaction
4.1.1 General overview of Eyring equation
Eyring equation provides a molecular level insight into reaction of interest that is reflected in the rate constant (k). According to Eyring equation, rate constant of a reaction,
� �( ∆ / ) Equation 4.1 k =
where � is transmission coefficient, � is Boltzmann constant, ℎ is Plank’s constant, T is the temperature in Kelvin.
−∆� is the change in free energy of activation for the given reaction, and R is the universal gas constant.
In a given reaction if two different products are formed with rate constant � and � , the ratio of rate constant, 254
∆∆ = � (∆ ∆ )/ = � Equation 4.2 where ∆� and ∆� are the change in free energy of activation for the formation of two products with rate constant � and � respectively.
Change in free energy, ∆� is given by the equation
∆� = ∆� − �∆� Equation 4.3 where ∆� and ∆� represents the change in enthalpy and entropy of the reaction.
Similarly, the change in free energy of activation is given by,
∆� = ∆� − �∆� Equation 4.4 where ∆� , ∆� are change in enthalpy of activation and entropy of activation respectively.
Substituting the Equation 4.3 and 4.4 in Equation 4.2 the differential activation in a given system can be represented by,
∆∆� = ∆∆� − �∆∆�
� ∆∆� ∆∆� �� = − Equation 4.5 � � ��
where ∆∆� represents differential entropy of activation between the two reactants and ∆∆� represents differential enthalpy of activation and ∆∆� is the differential activation free energy.
Product distribution depends upon the ratio of � /� where the major product formed will be the one with higher rate constant. So, if � /� > 1, product with the rate constant of formation � will be the major product. If � /� < 1, product with rate constant of formation � 255
will be the major product. Form Eyring equation the sign of �� (i.e. if � /� > 1 or � /� < 1) depends on the sign and magnitude of ∆∆� and ∆∆� .
∆∆ When ∆∆� is positive and is negative, �� will have a positive value (i.e. � /� > 1)
∆∆ When ∆∆� is negative and is positive, �� will have a negative value (i.e. � /� < 1)
∆∆� ∆∆ However, when both and have same sign (i.e. either both positive or both negative) or similar magnitude temperature might play a major role in determining the product
∆∆� ∆∆ distribution. For e.g. if and has positive values at lower temperatures, then magnitude
∆∆ ∆∆ of can override the magnitude of and vice versa. This is reflected in the temperature dependence of product distribution. If a product predominates due to higher contribution of
∆∆� ∆∆ 1-2 compared to , such reactions are termed as entropically controlled reactions.
4.1.2 Entropy control in a photochemical reaction
Inoue and co-workers demonstrated effect of differential entropy of activation (∆∆� ) for asymmetric photoreaction.1 They reported highly enantiodifferentiating Z-E photoisomerization of cyclooctene Z-200 (Scheme 4.1) in the presence of chiral polyalkyl benzene polycarboxylate sensitizers (201 and 202). Reaction involved the formation of exciplex between the sensitizer and cyclooctene. With bulky ortho substituted benzene carboxylate such as (-)-tetramenthy-1,2,4,5- benzenetetracarboxylate 201 or benzene hexacarboxylate 202 moderate enantiomeric excess of -
9.6 and -16.8 was observed. The reaction involved formation of singlet exciplex between the excited sensitizer and cyclooctene. However, quenching of excited state of sensitizer with R or S cyclooctene was diffusion controlled process. Enatio differentiating step involved relaxation of 256 exciplex through double bond isomerization. With bulky ortho substituted sensitizer rate of relaxation was hindered. This was reflected in the temperature dependent stereo selectivity. At higher temperature, the double bond isomerization was favored that contributed to the increased enantiomeric excess. This photoreaction involved entropy contribution for dictating the enantiomeric excess in the final product.
hν Sensitizer +
Z - 200 E - (-)-(R)-200 E - (+)-(S)-200
CO2R CH RO2C CO2R RO2C CO2R 3
R = CH3 RO2C CO2R RO2C CO2R 201 CO2R CH3 202
Scheme 4.1: Entropy controlled enantio differentiating isomerization of cyclooctene Z - 200 in the presence of bulky chiral sensitizer 201 and 202.
Mori and co-workers demonstrated diasteroslective Paternò-Büchi reaction of naphthyl aryl ethene 203 with 4-cyano aryl benzoate 204 derivative possessing a chiral auxiliary (Scheme
4.2).2 Reaction involved formation of exciplex that was governed by weak non-covalent interactions. Entropy played a major role in dictating the selectivity. Photoreaction resulted in the formation of endo-205 and exo-206 adduct with endo being the major diastereomer. With 203d which has bulky substituent (hexyl group) at the meta position of phenyl group, high diastereomeric excess (de) of 39% was observed in THF solvent. The selectivity was dictated by increased differential entropy of activation (∆∆� ). 257
1 R2O R OR2 R1 O O +
3 2 3 2
R CN CN O OR* 205 (2S, 3R) 205 (2R, 3S) endo
+ hν
CN CN CN
1 203 204 R R1 O O a) R = H R1 = + b) R = 2,6-Me2 c) R = 3,5-Me2 3 2 OR2 R2O 3 2 d) R = 3,5-Hex2 R2 = exo
206 (2S, 3R) 206 (2R, 3S)
Scheme 4.2: Entropy controlled Paternò-Büchi reaction of cyclooctene in the presence of bulky chiral sensitizer.
4.2 [3+2]-Photocycloaddition reaction
4.2.1 [3+2]-Photocycloaddition reaction of three membered rings
[3+2]-Photocycloaddition typically involve addition of three-atom unit with a two-atom unit to form five membered cyclic ring. Typically, three membered ring such as aziridne, aziridines, oxiranes, or cyclopropanes undergo [3+2]-photocycloaddition with alkene moiety
(Scheme 4.3). The reaction can also be induced by photoinduced electron transfer (PET).
Photoirradiation results in the formation of dipolarophile that adds to alkene to form five membered cyclic adduct. 258
X X X hν Y
X = N, O, C Y
X X X hν/PET Y X = N, O, C [sens] Y
Scheme 4.3: Three membered ring in [3+2] photocycloaddition.
Padwa and co-workers demonstrated irradiation of diphenyl aziridine 208 that resulted in the formation of nitrile ylide that adds to alkene in a diasteroslective fashion to form [3+2]- adduct 209 (Scheme 4.4).3
CN N N hν Ph 192 Ph Ph C H Ph C N 6 6 C H Ph 208 Ph 6 6 209 CN
de = 80%
Scheme 4.4: Aziridine in [3+2]-photocycloaddition of aziridine 208.
4.2.2 Meta-cycloaddition reaction
Meta-cycloaddition involves [3+2] cycloaddition of benzene ring with alkene to form complex polycyclic architecture (Scheme 4.5).4 The product of meta-cycloaddition consists of three new rings with three new sigma bond formations with a minimum of 4 stereo-centers. 259
hν +
8 49 210
Scheme 4.5: Meta-cycloaddition reaction
This reaction has been used for the synthesis of several complex natural products.5,6 One of the classic synthesis of natural product using meta cycloaddition was reported by Wender and co-workers in the synthesis of a-cedrene .5,6 Irradiation of solution of anisole derivative 211 in pentane solution resulted in the formation of meta-cycloadduct 212a and 212b which were later subjected to further reaction to form a-cedrene (Scheme 4.6). The key step involved in the reaction is the first photochemical step in which four new chiral centers are formed with excellent relative stereochemistry.
OMe MeO
hν +
OMe 211 212a 212b
1. Br2 , CH2Cl2 2. Bu3SnH
H OMe
NH2NH2, KOH, O (HOCH2CH2)2O, 200 °C
213 α-cedrene 214
Scheme 4.6: Meta photocycloaddition in the synthesis of a-cedrene 214. 260
Porco and co-workers reported [3+2]-photocycloaddition in the synthesis of natural product methyl rocaglate7 that has anticancer property (Scheme 4.7). The key step involved an excited state intramolecular hydrogen atom transfer (ESIT) of 215 to form diploarophile that reacted with the alkene derivative 216 to form the diastereomer 207a and 207b which was subjected to further reaction to form final product (Scheme 4.7).
O
R O 2 O OMe OH HO OMe O OMe O Ph MeO OH O CO2Me CO2Me OH hν [3+2]
MeO O MeO O Me O MeO O O OMe 215 OMe
217a OMe 217b OMe
Ph CO2Me
216
Scheme 4.7: Meta photocycloaddition in the synthesis methyl rocaglate 217.
4.3 [3+2]- Photocycloaddition of phenylketone enamide 156b
In Chapter 2 we have discussed our study on phenyl ketone 156b tethered atropisomeric enamide compounds for Paternò-Büchi reaction. We reported that the compound 156b undergoes normal Paternò-Büchi reaction under direct irradiation. However, under sensitized conditions with xanthone as triplet sensitizer, energy transfer from sensitizer occurred leading to transposed
Paternò-Büchi reaction (cf. Chapter 2). It can also result in intramolecular energy transfer from enamide chromophore to the carbonyl group, so that excited carbonyl group does add to the enamide chromophore.
During our investigation with 156b we observed that the exclusive formation of [2+2]- adduct (oxetane product) was observed only at low temperature of -30 °C. At room temperature, we observed [3+2]-cycloaddition product along with [2+2] photoproduct.8 261
The formation of the [3+2]-photocyclization product was quite significant as it involves the formation of two new sigma bonds with three new stereo centers (Scheme 4.8). Developing a strategy where two entirely different reactions viz. ([2+2] or [3+2]) photocycloaddition product) can be performed from same starting material, just by changing temperature would be quite interesting in terms of synthetic utility and mechanistic aspects. It will also provide a handle for understanding the factors responsible for chemoselectivity in excited state transformation.
O O O N O N O N N HO O O
OMe 156b 156h 157b 218
MeO O O O N N N O Br HO MeO O
OMe
157h 219 156a 220
Chart 4.1: Compounds utilized for the study of temperature effect on [2+2] vs [3+2] photocycloaddition and the precursors used for their synthesis.
Optimized reaction conditions were developed for [2+2]-photocycloaddition and/or
[3+2]-photocycloaddition by employing various solvents and reaction temperatures. With phenylketone 156b exclusive formation of [2+2]-adduct 157b at low temperature (i.e. -30 °C) was observed. Whereas, at room temperature mixture of [2+2] and [3+2]-products (157b and 218 262 respectively) were observed. This directed our interest to carry out detailed investigation on temperature effect on the photoreaction involving 157b.
To begin our investigation of [2+2] vs [3+2] photocycloaddition of phenylketone 156b tethered atropisomeric enamide, we explored the reaction in MeCN at various temperatures under xanthone sensitization. The products were characterized by carrying out the reaction at room temperature. The formation of [3+2]-photoadduct 218 was confirmed by single crystal
XRD analysis and by NMR spectroscopy (refer to experimental section).
Before varying the temperature of reaction, large scale photoreaction was carried out at room temperature to isolate the photoproduct.
The large scale photoreaction was carried out with 80 mg scale of phenyl ketone substrate under ~ 350 nm light irradiation in the presence of 20 mol% of xanthone sensitizer in acetonitrile solution (Scheme 4.8) (details of reaction conditions are described in the experimental section).
Reaction was monitored by crude NMR for complete disappearance of starting material. After
5 h, reaction got completed and both the pure products (157b and 218) were isolated by
Combiflash followed by the characterization with NMR spectroscopy. [2+2] and [3+2] photocycloaddition products (157b and 218) were obtained with an isolated yield of 36% and
18% respectively. The isolated product was characterized by 1H-NMR, 13C-NMR spectroscopy and single crystal XRD structure determination. 263
O O O N O hν ~ 350 nm N N Xanthone HO O Solvent, t (h), T (°C) +
156b 157b 218
Scheme 4.8: Photoreaction of enamide 156b to form [2+2]-photoproduct 157b and [3+2]- photoproduct 218.
The ratio of [2+2] to [3+2] adduct was monitored by the analysis of crude NMR of reaction mixture after a specific time of photoreaction and at a given temperature.
Figure 4.1 shows 1H-NMR spectroscopic analysis the reaction mixture consisting of
[2+2]-photoproduct 157b and [3+2]-photoproduct 218 adduct and enamide 156b. The proton resonance of Ha of [2+2]-photoproduct 157b and Hb of [3+2]-photoproduct 218 appeared as expected as a doublet of doublet around 4.89 and 4.26 ppm respectively (Figure 4.2). The change in intensity of these proton resonance signal were monitored for the reaction that was carried out at different temperatures (Figure 4.2). 264
[3+2] product 218
[2+2] product 157b
Phenyl ketone 156b
Figure 4.1: 1H-NMR spectra of 157b and 218 cycloadduct along with starting material of phenylketone 156b. 265
At -40 °C
At -5 °C
At 25 °C
At 70 °C
Ha O O Hb O N N HO
157b 218b
Figure 4.2: Expanded region of crude reaction mixture NMR spectra depicting 157b and 218b cycloadduct resonances of the bridge head protons “Ha” (in 157b) and “Hb” (in 218b) at different temperatures.
266
At room temperature, the ratio of 157b vs 218 adduct in acetonitrile solvent was found to be 1:0.8. At lower temperature of -40 °C the intensity changed to 1:0.1 with the exclusive formation of [2+2] adduct. Upon increasing the temperature, the [3+2] adduct was favored. At
-5 °C the ratio of 157b to 218 was to 1:0.5 and at 70 °C the ratio 1:1.1 which clearly indicated that 218 was formed at higher temperature.
Table 4.1:Effect of temperature on formation of 157b and 218.
157b:218 Sr. T T 1/T Time ([2+2]: Solvent 157b /218 ln (157b /218) No (°C) (K) (K-1) (h) [3+2])
1 MeCN -40 233 0.0043 2 1:0.1 8.5 2.14 2 MeCN -5 268 0.0038 2 1:0.5 2 0.693 3 MeCN 25 298 0.0033 2 1:0.8 1.25 0.223 4 MeCN 70 343 0.0029 2 1:1.1 0.86 -0.150
Eyring parameter (DDS‡ and DDH‡) was extracted from the Eyring plot (Figure 4.3) for the chemoselective formation of [2+2] vs [3+2] product (i.e. 157b vs 218) in acetonitrile as solvent. Inspection Eyring plot (Figure 4.3) for the formation of 157b vs 218 showed that in
∆∆ = ∆∆ acetonitrile the intercept -5.2 and slope = 1.66 cal/mol/K. This implies that
∆∆� = -10.3 cal/mol/K and ∆∆� = 3.3 cal/mol. This showed that reaction could be sensitive to temperature variations. 267
‡ DDS = - 10.03 cal/mol/K ‡ DDH = 3.3 cal/mol
Figure 4.3: Eyring plots for [2+2] -photoproduct 157b vs [3+2]-photoproduct 218 at different temperature in acetonitrile solvent.
Due to the limit of boiling point of acetonitrile (82 °C), further increase in temperature for the reaction was carried out in high boiling solvents such as in toluene (B.P = 110 °C) or in
DMF (B.P = 153 °C). At higher temperature with the ratio [3+2]-photoproduct 218 was further increased. At 130 °C in DMF, the ratio of 157b : 218 changed to 0.2:1.0 (Table 4.2).
Table 4.2: Effect of temperature on [2+2] vs [3+2] product formation (157b vs 218) in toluene and DMF.
Sr. No Solvent T (° C) T (K) 1/T (K-1) Time (h) 157b: 218 1 Toluene 105 378 0.0026 2 1:0.4 2 DMF 130 403 0.0025 0.5 0.2:1
As we had established that the benzoyl chromophore in 157b is excited (based on our results in Chapter 2) we investigated the effect of electron donating group on phenyl substitution
(Scheme 4.9). 268
MeO O O O N O hν ~ 350 nm N N Xanthone HO O Solvent, t (h), T (°C) MeO +
OMe 156h 157h 219
Scheme 4.9: Photoreaction enamide 156h to form [2+2]-photoproduct 157h and [3+2] - photoproduct 219.
The p-methoxy substituted enamide 156h derivative was irradiated with 350 nm light in the presence of xanthone sensitizer (20 mol%) in acetonitrile solvent for 2 h (Scheme 4.9). After
2 h, crude product was monitored by 1H-NMR spectroscopy. The ratio of 157h to 219 was 1:0. 4 means that electron donating substituent favors the formation [2+2] product. This observation can be rationalized based on the fact that electron donating substituent stabilize the p system of carbonyl group which results in lowest excited state localized on carbonyl group preferring the
[2+2] reaction pathway. 269
4.3.1 Plausible mechanism
* H hν ~ 350 nm O O N O Xanthone N O N O (20 mol%) O
Ph
156b excited ketone BR-1-156b
H
O O O N N HO
157b 157b BR-2-156b (XRD structure)
Scheme 4.10: Plausible mechanism for the formation of [3+2]-photocycloaddition product 157b.
The formation of [3+2]-photocycloaddition product can be visualized in terms of the plausible mechanism in Scheme 4.10. Triplet sensitization with xanthone sensitizer can generate excited state of phenyl ketone 156b where excited state could be localized on phenyl ketone tether. The first bond formed between carbonyl carbon of phenyl ketone tether and enamide chromophore results in the formation of biradical BR-1-156b which undergoes cyclization with phenyl ring to form five membered ring biradical BR-2-156b. This step follows re- aromatization/ hydrogen abstraction by oxygen centered radical to form [3+2] adduct 157b. 270
4.4 Conclusion
By varying temperature, we have uncovered a new photoreaction pathway in which [2+2] photocycloaddition can be inhibited in favor of [3+2] photocycloaddition. Based on Eyring parameters, the formation of [3+2] is likely directed by entropic factors.
4.5 Experimental section
All commercially obtained reagents/solvents were used as received; chemicals were purchased from Alfa Aesar®, Sigma-Aldrich®, Acros organics®, TCI America®, Mallinckrodt®, and Oakwood® Products, and were used as received without further purification. Unless stated otherwise, reactions were conducted in oven-dried glassware under nitrogen atmosphere. 1H-
NMR and 13C-NMR spectra were recorded on Varian 400 MHz (100 MHz for 13C) and on 500
MHz (125 MHz for 13C) spectrometers. Data from the 1H-NMR spectroscopy are reported as chemical shift (δ ppm) with the corresponding integration values. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s
(singlet), b (broad), d (doublet), t (triplet), q (quartet), m (multiplet) and virt (virtual). Data for
13C NMR spectra are reported in terms of chemical shift (δ ppm).
When necessary, the compounds were purified by combiflash equipped with dual wavelength UV-Vis absorbance detector (Teledyn ISCO) using hexanes:ethyl acetate as the mobile phase and Redisep® cartridge filled with silica (Teledyne ISCO) as stationary phase. In some cases, compounds were purified by column chromatography on silica gel (Sorbent
Technologies®, silica gel standard grade: porosity 60 Å, particle size: 230 x 400 mesh, surface area: 500 – 600 m2/g, bulk density: 0.4 g/mL, pH range: 6.5 – 7.5). Unless indicated, the 271
Retardation Factor (Rf) values were recorded using a 5-50% hexanes:ethyl acetate as mobile
® phase and on Sorbent Technologies , silica Gel TLC plates (200 mm thickness w/UV254).
Photophysical Methods.
Spectrophotometric solvents (Sigma-Aldrich®) were used whenever necessary unless or otherwise mentioned. UV quality fluorimeter cells (with range until 190 nm) were purchased from Luzchem®. Absorbance measurements were performed using a Shimadzu® UV-2501PC
UV-Vis spectrophotometer.
4.5.1 Synthetic protocol for 4-methoxy phenyl ketone derivative 220
Br MgBr Mg, I2, THF 40 °C, 30 min.
OMe OMe 220
MgBr
1.
OMe THF, 0 °C - r.t O N 4 h N O O O 2. DMP DCM, 0 °C, 1 h
OMe 156a 156h
Scheme 4.11: Grignard reaction for the synthesis of 4-methoxy phenylketone derivative 156h.
Grignard reagent was prepared as per the literature report. Magnesium turnings (0.9456 g,
39.4 mmol, 1.5 equi.), catalytic amount of iodine crystal was taken in a dry flask containing 10 272 mL of dry THF. 4-bromoanisole 220 (3.3 mL, 26.2 mmol, 1.0 equi.) was added dropwise over 15 min. Mixture was warmed gently to 40 °C and then allowed to reflux under nitrogen atmosphere.
Reaction mixture was stirred for further 30 min. and formation of Grignard reagent was observed with the consumption of Magnesium turnings. The concentration of resulting solution was ~2M.
To the alcohol (150 mg, 0.4445 mmol, 1.0 equi.) in 5 mL of DCM, Dess-Martin periodane
(DMP) was added the reaction was carried out for an hour, monitored by TLC. The crude product was purified by Combiflash.
Product formation was confirmed by NMR spectroscopy.
Yield = 59% 273
1 H-NMR (500 MHz; CDCl3): δ 7.93 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 3H), 7.01 (s, 1H),
6.92-6.90 (m, 3H), 6.29 (d, J = 4.9 Hz, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H),
4.00 (d, J = 17.2 Hz, 1H), 3.86 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H), 2.01 (s, 2H), 1.24 (s, 3H), 1.01
(s, 3H).
O OMe
N
O
Figure 4.4: 1H-NMR spectra of 4-methoxy phenylketone derivative 156h. 274
13-C NMR (126 MHz; CDCl3): δ 196.0, 181.7, 163.6, 133.8, 132.2, 131.7, 130.70, 130.59,
129.69, 129.54, 117.47, 117.47, 113.77, 113.77, 55.5, 45.9, 41.9, 23.5, 23.3, 21.1, 17.9
O OMe
N
O
Figure 4.5: 13C-NMR spectra of 4-methoxy phenylketone derivative 156h. 275
4.5.2 General irradiation procedure and characterization of photoproducts
R1 O O O hν ~ 350 nm N O N N Xanthone (20 mol %) HO O 1 Solvent, t (h), T (°C), N2 R +
R1 156b : R1 = H 157b : R1 = H 218 : R1 = H 1 1 1 220 : R = OCH3 157h : R = OCH3 219 : R = OCH3
Scheme 4.12: Photoreaction of phenylketone derivative 156b and 220.
A N2 saturated solution of phenyl ketone derivative 156b in MeCN (1mg/1mL or 2.5-4.1 mM) with xanthone sensitizer (20 mol%) was irradiated in a Rayonet reactor equipped with ~350 nm bulbs until the reaction was complete as monitored by the 1H-NMR spectroscopy (and TLC).
The large-scale photoreactions were performed as batches on the same concentration (8 ×
10 mL test tubes per batch) using merry-go-round apparatus. After the reaction, the solvent was evaporated under reduced pressure and the residue was purified by combiflash to get the pure product. The Rf of most of the photoproducts and their starting materials were similar, so 1H-
NMR spectroscopy was used simultaneously to monitor the reaction.
Low temperature reactions (-40 °C and -5 °C) were performed using an immersion cooler. Solution of reactants in a Pyrex test tube was kept in acetone bath inside the Rayonet reactor with an immersion cooler set at the required temperature. Acetone bath was maintained in a Pyrex jacket. Proper care was taken to make sure that temperature was not reduced below the freezing point of acetone or ice formation during the irradiation time which can block the 276 penetration of light into the reaction mixture. The Pyrex test tube with reaction mixture was kept for at least 15 min. before irradiation for equilibration.
For high temperature (70 °C in acetonitrile, 105 °C in toluene, 130 °C in DMF), reaction was performed in a in Silicone oil bath. Pyrex test tube containing degassed solution of reaction mixture was immersed in Silicone oil bath in a Pyrex beaker. Heating was performed using a hot plate and temperature of oil bath was constantly monitored. This setup was kept inside the
Rayonet reactor for irradiation. 277
1 H-NMR (500 MHz; CDCl3): δ 7.40-7.36 (m, 4H), 7.40-7.30 (m, 5H), 7.04 (d, J = 0.8 Hz, 1H),
6.84 (t, J = 0.6 Hz, 1H), 4.90 (d, J = 3.9 Hz, 1H), 4.09 (d, J = 3.9 Hz, 1H), 3.09 (q, J = 19.1 Hz,
3H), 2.33 (d, J = 5.0 Hz, 6H), 1.36 (s, 4H), 1.36 (s, 4H), 1.19 (s, 3H), 1.19 (s, 4H).
O N
O
Figure 4.6: 1H-NMR spectra of [2+2]-photocycloaddition product 157b. 278
13 C-NMR (100 MHz, CDCl3, δ ppm): 179.5, 143.98, 137.4, 134.94, 133.4, 133.3, 129.95, 128.9,
127.8, 126.7, 124.1, 91.5, 83.1, 62.3, 45.5, 43.4, 22.3, 21.4, 17.6 and 16.5.
* O N
O Ph
* = solvent
Figure 4.7: 13C-NMR spectra of [2+2]-photocycloaddition product 157b 279
1 H-NMR (500 MHz; CDCl3): δ 7.40-7.30 (m, 5H), 7.04 (d, J = 0.8 Hz, 1H), 6.84 (t, J = 0.6 Hz,
1H), 4.90 (d, J = 3.9 Hz, 1H), 4.09 (d, J = 3.9 Hz, 1H), 3.09 (q, J = 19.1 Hz, 3H), 2.33 (d, J = 5.0
Hz, 6H), 1.36 (s, 4H), 1.19 (s, 3H).
O
N
OH
Figure 4.8: 1H-NMR spectra of [3+2]-photocycloaddition product 218. 280
13-C NMR (126 MHz; CDCl3): δ 177.3, 146.2, 141.2, 137.1, 134.0, 133.2, 132.0, 130.4, 129.3,
128.9, 127.5, 126.8, 123.9, 89.2, 71.3, 52.0, 44.7, 42.0, 30.3, 23.5, 21.3, 18.0
O
N
OH
Figure 4.9: 13C-NMR spectra of [3+2]-photocycloaddition product 218. 281
4.5.3 XRD data
Table 4.3: X-ray structural parameters of 218
Formula C22 H23 N O2 ß [Å] 90
FW 333.43 γ [Å] 90
3 cryst. size_ma [mm] 0.33 V [Å ] 1727.80(10) 3 cryst. size_mid [mm] 0.07 ρcalc [g/cm ] 1.289 -1 cryst. size_min [mm] 0.04 µ [cm ] 0.661 CuKα (λ = cryst. system Radiation Type orthorhombic 1.54178)
Space Group, Z P212121 F(000) 716.0 a [Å] 9.0972(3) no of measured refl. 10864 b [Å] 11.3927(4) no of indep. refl. 2969 c [Å] 16.6709(6) no of refl. (I ≥ 2σ) 0.0329(2677) a 0.0451 R1/wR2 (I ≥ 2σ) [%] Resolution [Å] 0.84 /0.1231 a R1/wR2 (all data) [%] 0.0506 R1/wR2 (I ≥ 2σ) 0.0451 /0.1256 [%] /0.1231
OH O N
218 218
Figure 4.10: Single crystal XRD structure of [3+2]-photocycloaddition product 218. 282
4.6 References
(1) Inoue, Y.; Ikeda, H.; Kaneda, M.; Sumimura, T.; Everitt, S. R. L.; Wada, T. Entropy-
Controlled Asymmetric Photochemistry: Switching of Product Chirality by Solvent. J. Am.
Chem. Soc. 2000, 122, 406–407.
(2) Nagasaki, K.; Inoue, Y.; Mori, T. Entropy-Driven Diastereoselectivity Improvement in the
Paternò–Büchi Reaction of 1-Naphthyl Aryl Ethenes with a Chiral Cyanobenzoate through
Remote Alkylation. Angewandte Chemie International Edition 2018, 57, 4880–4885.
(3) Mueller, Felix.; Mattay, Jochen. Photocycloadditions: Control by Energy and Electron
Transfer. Chem. Rev. 1993, 93, 99–117.
(4) Cornelisse, Jan. The Meta Photocycloaddition of Arenes to Alkenes. Chem. Rev. 1993, 93,
615–669.
(5) Chappell, D.; Russell, A. T. From α-Cedrene to Crinipellin B and Onward: 25 Years of the
Alkene–Arene Meta -Photocycloaddition Reaction in Natural. Organic & Biomolecular
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(2), 615–669.
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(8) Kumarasamy, E.; Raghunathan, R.; Kandappa, S. K.; Sreenithya, A.; Jockusch, S.; Sunoj,
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283
5 CHAPTER: 5 CONCLUSIONS
Using light as a green reagent for inducing chemical reaction provides an alternate strategy for developing reactions that are complimentary to established methodologies. It provides convenient access to complex molecular architectures that are difficult to attain by thermal reactions. Unlike thermal reactions, the high energy and short lifetime of excited state(s) presents considerable challenges to control photochemical reactions. By controlling the excited state characteristics of chromophores, the reactivity and hence, the selectivity could be manipulated.
This dissertation explores strategies to manipulate the excited state reactivity of organic chromophores and uncover new chemical reactivity from the excited states. The approach was directed to control the cycloaddition reactions involving alkenes, carbonyls and imines.
Chapter 1 provides an overview of organic photochemical reactions. General outline of basic photochemical principles are discussed. It also includes some traditional organic photochemical reactions described in the context of historical perspectives. Methodologies for controlling photochemical asymmetric synthesis and the strategies developed to address the challenges included in asymmetric photoreactions are discussed.
Chapter 2 highlights the discovery of a new photoreaction that was labeled as Paternò-
Büchi reaction. Unlike traditional Paternò-Büchi reaction, where excited state is localized in the carbonyl group, we were able to design the systems in which the excited state can be localized on alkene chromophore. The excited alkene was directed to react with a ground state carbonyl group leading to Transposed Paternò-Büchi reaction. Details of our design strategy, photochemical, photophysical and computational studies are discussed in this chapter. Application of Transposed 284
Paternò-Büchi reaction to overcome some common challenges in traditional Paternò-Büchi reaction are also discussed.
Chapter 3 highlights the discovery of a new photoreaction known as Aza Paternò-Büchi reaction. The reaction involves an excited alkene adding to a ground state imine. In general, imine photocycloaddition was considered to be quite challenging due to several reaction pathways of imines in the excited state. We have explored a new strategy for imine [2+2]- photocycloaddition by a novel design of reacting chromophore to avoid excitation of imine double bond. This reaction was considered as an application of Transposed Paternò-Büchi reaction which is discussed in the second chapter. Chiral induction in Aza Paternò-Büchi reaction was achieved by using atropisomeric imine substrates. Details of photophysical and mechanistic investigations are also discussed in this chapter. This strategy provides a one step access to azetidines by a light induced reaction.
Chapter 4 discusses temperature effect for the photocycloaddition of carbonyl group with alkenes. By controlling entropic factors, the photoreactivity between [2+2] vs [3+2] photocycloaddition was manipulated. The reaction profile was deciphered using Eyring parameters.
In this dissertation, two new photoreactions viz. Transposed Paternò-Büchi reaction and
Aza Paternò-Büchi reaction were developed. The newly developed photochemical pathways open the scope and applicability of light induced transformations.