INVESTIGATIVE PHOTOCHEMISTRY: ELUCIDATING THE MECHANISM OF THE PHOTO-FAVORSKII REARRANGEMENT By C2008 Kenneth F. Stensrud Submitted to the Department of Chemistry and the Faculty of the Graduate School of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy ______________________________ Chairperson ______________________________ ______________________________ ______________________________ ______________________________ Date Defended: ________________ The dissertation committee for Kenneth F. Stensrud certifies that this is the approved version of the following dissertation: INVESTIGATIVE PHOTOCHEMISTRY: ELUCIDATING THE MECHANISM OF THE PHOTO-FAVORSKII REARRANGEMENT Dissertation Committee: ______________________________ Chairperson ______________________________ ______________________________ ______________________________ ______________________________ Date Approved: ________________ ii Abstract Kenneth F. Stensrud, Ph.D. Department of Chemistry, April 2008 University of Kansas The p-hydroxyphenacyl chromophore (pHP) is a versatile phototrigger for an assortment of biological nucleofuges, such as γ-aminobutyric acid (GABA). The photochemistry is trenchant; irradiation discharges the nucleofuge and induces rearrangement of pHP, analogous to the ground state Favorskii rearrangement. Structure-reactivity relationships were explored with pHP GABA’s. Electron donating groups lowered the release efficiency, Φdis, relative to the unsubstituted analog. Electron withdrawing carbonyl groups attenuated Φdis. Fluoro moieties modulated the pKa of pHP; protonated pHP manifested higher Φdis than their conjugate base counterparts. The reactive excited states were determined as triplets by Stern-Volmer quenching and laser flash photolysis studies. The triplet lifetimes were ~ 10-9 s with release rate constants of 107 to 108 s-1. Auxochrome substitutions lengthened the λmax of pHP but lowered Φdis. Added perchlorate salts markedly improved Φdis for pHP GABA’s, imputing intermediate ion-radical pairs. Comprehensive photo-Favorskii mechanisms were posited for protonated and conjugate base forms of pHP GABA. iii Acknowledgements There have been frequent comments regarding my use of flowery, poetic words instead of those deemed appropriate for scientific writing. Though I have learned to distinguish one from the other while composing this dissertation, I find it truly risible that, at this time, words fail me when appositely expressing my gratitude to my advisor, Professor Richard Givens. Dr. Givens equanimity in dealing with my oft hair-brained ideas and digressions cannot be understated. My motivations to work long hours at solving our research problems originated from his encouragements and well considered proposals. Honestly, I shouldn’t continue to indite a synopsis of his qualities, as they will present as mere platitudes. I can only state with certainty that Dr. Givens will always remain close to my heart for everything he has passed on to me both as a scientist and a man of utmost integrity. My parents, Ken and Donna, have sacrificed more than I can fathom to ensure that their son, the opsimath, would succeed in his endeavors. I am grateful for your closeness and support. Mom and dad, my love for you will transcend this life. My brother Dan has always been there for me irrespective of the difficulty of the times. Dan, I look forward to growing old with you as both my brother and best friend. My wife, Beth Stensrud, was the linchpin in my success as a graduate student. The single greatest event in my life was meeting you my first semester at KU. You were my foundation, my stimulus to endure time of tumult. I am dubious that I would iv have persevered without you. Beth, from you I have recognized the existence of angels. I owe a debt of gratitude to Dr. Todd Williams for his willingness to instruct me on the applications of the QQQ and furthermore permit me to utilize the instrument without restrictions over the past two years. I can honestly state that I would have completed a tenth of the amount of work if I did not have access to instrument and your exhortations. Todd, your succor will always be remembered and revered. Professor Abraham Yousef was my antecedent in the laboratory. Your forbearance and willingness to instruct when I was maladroit will never be forgotten. Abraham, I owe much of my success in the laboratory to you, your mundane disposition was appreciated more than you can know. I hope we can stay in touch throughout the years. To Dr. Elizabeth Cope, you were a friend and lab colleague. Beth, I will never forget the long hours and weekends we spent in the laboratory, imbued with successes, failures, and insightful talks. I appreciated this. It is eerie now when I come into lab on the weekends and I don’t see you. To Dr. Gerry Lushington, Professor Jakob Wirz, Dr. Dominik Heger and Professor Karl Kandler, thank you for your collaborative efforts. The information that you gleaned facilitated the solution of my research problems. v John Hershberger - we came in together and we will go out together. Through good and bad times, times of confusion and consumption, our experiences will never be forgotten. vi Table of Contents page Abstract iii Acknowledgements iv List of Figures xi List of Schemes xvii List of Tables xxi List of Equations xxiv Glossary of Chemical Compounds Studied xxv Introduction 1 I. Early Investigations of The Favorskii Rearrangement 1 II. Bordwell’s Contributions 5 A. Rate, Isotope and Nucleofuge Studies 6 B. Substituent, LFER, Salt, Media Studies 11 C. Ramberg-Backland Analogy-Role of Orbital Overlap 17 D. Influence of α-Substituents 21 E. Evidence for a Dipolar Intermediate 29 F. Studies in Stereochemistry 32 III. Computational Investigations 37 IV. Variations to the Classical Favorskii Rearrangement 44 vii V. The Photochemical Version of the Favorskii Rearrangement 46 Statement of Problem 92 Results 94 I. Synthetic Methodologies 94 A. pHP GABA Series and 4-Fluorophenacyl GABA 94 B. pHP Glu Series 101 C. Other pHP Caged Amino Acids 102 D. pHP Deoxycholic Acid 104 E. pHP Diethyl Phosphonate 106 F. pHP F 106 G. 5-Acetylsalicylic Acid and Salicylamide GABA Series 107 H. 5-Acetylsalicylic Acid Alkanoyl Compounds 113 I. α-alkyl-pHP diaseteromers 114 J. FITC-DOC 116 II. Exploratory Photochemistry 117 A. 1H NMR Analysis, pHP GABA Series 119 B. 1H NMR Analysis, α-Alkyl-pHP GABA Series 125 C. 1H NMR Analysis, pHP Glu Series 128 D. 1H NMR Analysis, Other pHP-Caged Amino Acids 130 E. 1H NMR Analysis, pHP Deoxycholic Acid 131 F. 1H NMR Analysis, pHP Diethyl Phosphonate 133 G. 1H NMR Analysis, pHP F 133 viii H. 1H NMR Analysis, 5-Acetylsalicylic acid GABA Series 135 I. 1H NMR Analysis, 5-Acetylsalicylic Acid Alkanoyls 137 J. 1H NMR Analysis, α-Alkyl pHP Diastereomers 140 K. 19F NMR Analysis, pHP and 5-Acetylsalicylic Acid GABA’s 142 III. UV-Vis Spectroscopic Studies 145 A. pHP GABA Series and 4-Fluorophenacyl GABA 145 B. pHP Glu Series 153 C. Other pHP-Caged Amino Acids, DOC and Fluoride 154 D. 5-Acetylsalicylic Acid GABA Series and Alkanoyls 154 E. α-Alkyl-pHP Diastereomers 156 IV. Fluorescence Spectroscopic Studies 156 V. Time Correlated Single Photon Counting Studies 158 VI. Quantitative Photochemical Analysis 159 A. pHP GABA Series at 300 nm 160 B. pHP GABA Series at 350 nm 168 C. pHP Glu Series 169 D. Other pHP-Caged Amino Acids 170 E. pHP DOC and Fluoride 171 F. 5-Acetylsalicylic Acid GABA Series and Alkanoyls 171 G. α-Alkyl-pHP Diastereomers 173 VII. Stern-Volmer Quenching Studies 174 VIII. Computational Studies 176 ix A. ClogP Calculations 177 B. Energies and Geometries of Triplet Biradicals 179 C. Spin and Charge Density Calculations 181 IX. Laser Flash Photolysis Studies 183 Discussion 198 A. Synthetic Strategies 198 B. General Photochemistry 201 C. Preliminary Mechanistic Studies 203 D. Substituent Effects on the Photo-Favorskii Rearrangement 209 E. Miscellaneous Substituent Effects on pHP GABA Photochemistry 216 F. Substituent Effects on 5-acetylsalicylic acid GABA derivatives 221 G. Nucleofuge Effects on the Photo-Favorskii Rearrangement 221 H. Nucleofuge Effects - Linear Free Energy Relationships 223 I. Media Effects on the Photo-Favorskii Rearrangement 226 J. Salt and Ionic Strength Effects 231 K. Rationalized Mechanism of the Photo-Favorskii Rearrangement 240 L. Biological Studies 244 M. Future Studies 248 Conclusion 251 Experimental 255 x List of Figures Figure 1. Diphenylcyclohexanones examined in the Favorskii reaction. 6 Figure 2. A potential energy illustration of the semibenzilic rearrangement process, revealing relative energies (in kcal/mol) of stationary points on the reactive surface that were calculated at the HF/6-31G* level. 40 Figure 3. A potential energy surface diagram of the cyclopropanone rearrangement mechanism, revealing relative energies (in kcal/mol) of stationary points on the reactive surface that were calculated at the HF/6-31G* level. 43 Figure 4. Left: Time dependent decay profile of pHP diethyl phosphate (3114) band ~1600 cm-1 with ns 3TR. Right: Time dependent decay profile of 3114 band ~1600 cm-1 with ns 3TR. 70 Figure 5. Time dependent decay profile of 3110 at ~1600 cm-1 in ns-3TR spectra. Circles indicate degassed, triangles open air, and squares oxygen. 72 Figure 6. Left: 1) Bottom - psTR3 spectrum of 115 in water. 2) Top - psTR3 spectrum of 115 in water. Right: 1) Bottom - psTR3 spectrum of 115 in buffer, pH = 9.00. 2) Top - psTR3 spectrum of 115 in buffer, pH = 9.00. 75 Figure 7. DFT determined, optimized geometry and bond distances (Ǻ) of 3115 in water. 77 Figure 8. Stern Volmer analysis of 3114 lifetimes as a function of water concentration, in percentage. 81 Figure 9. Phillips’ proposed structure of unknown, M, as a solvation/contact ion pair complex. 84 Figure 10. Step-scan FTIR of 121 in CD3CN (2% D2O) at 50 ns (red) and 1µs (blue) delay. 89 3 Figure 11. Plot of kobs of 114 vs. mole fraction of deuterium in degassed, o 10% aq. CH3CN at 25 C. 90 xi Figure 12.