ABSTRACT ZHANG, SHAOFEI. Synthesis of Bacteriochlorins and the Full Skeleton of Bacteriochlorophylls. (Under the direction of Professor Jonathan S. Lindsey.) Bacteriochlorins, the core macrocycle ring of natural bacteriochlorophylls, are characterized by their ability to absorb near infrared light (700 – 900 nm), which makes them attractive candidates in variety of photophysical studies and applications. The previously established de novo synthesis, which relies on the acid-catalyzed self-condensation of dihydrodipyrrin–acetal, provides access towards diverse bacteriochlorins, but has its limitations. This dissertation describes the development of new strategies for bacteriochlorin synthesis. Firstly, a route towards previously unknown tetra-alkyl bacteriochlorins (e.g., alkyl = Me, or –CH2CO2Me) is established (Ch. 2). Secondly, explorations of synthetic approaches to unsymmetrically substituted bacteriochlorins through electrocyclic reactions of linear tetrapyrrole intermediates are described. Four new unsymmetrically substituted bacteriochlorins and one new tetradehydrocorrin were produced, albeit in low yields (Ch. 3). Thirdly, a new method to construct bacteriochlorin macrocycle with concomitant Nazarov cyclization to form the annulated isocyclic ring, is established. Five new bacteriochlorins, which are closely anlogues of bacteriochlorophyll a, bearing various substituents (alkyl/alkyl, aryl, and alkyl/ester) at positions 2 and 3 and 132 carboalkoxy groups (R = Me or Et) were constructed in 37−61% yield from the bilin analogues (Ch. 4). Taken together, these studies expand the scope of available bacteriochlorins for fundamental studies and applications, and provide the synthetic pathway to full skeleton of bacteriochlorophylls. © Copyright 2017 by Shaofei Zhang All Rights Reserved Synthesis of Bacteriochlorins and the Full Skeleton of Bacteriochlorophylls by Shaofei Zhang A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry Raleigh, North Carolina 2017 APPROVED BY: _____________________________ _____________________________ Jonathan S. Lindsey David Shultz Chair of Committee _____________________________ _____________________________ Reza A. Ghiladi Joshua G. Pierce DEDICATION To my wife Kaimeng and my son Jason ii BIOGRAPHY Shaofei Zhang was born in Baoji, China in 1988. He received his B.Sc. degree in chemistry from Peking University, in 2011, after conduction research under the guidance of Professor Yuguo Ma and Jianbin Huang. Upon entering North Carolina State University in 2011 as a graduate student in chemistry, he joined the laboratory of Professor Jonathan S. Lindsey where he has been working on synthesis of tetrapyrrole macrocycles. iii ACKNOWLEDGMENTS The heart and beauty of synthesis chemistry lies in its creative nature. The request to the designed molecule is a long-term adventure filled with challenges, frustration, joys and opportunities. Luckily, I am not alone in this journey. First, I would like to thank my advisor and mentor, Dr. Jonathan Lindsey, for his guidance, encouragement and support. Besides, I would like to thank every faculty and staffs that I worked with in our chemistry department, for their teaching, assistance and collaboration. Also, I am grateful to work with all past and present members in our lab. I will treasure our friendship forever. At last, there are no words to express how grateful I am and how much I love for my family. iv TABLE OF CONTENTS LIST OF TABLES………………………………………………………………………....viii LIST OF FIGURES………………………………………………………………………ix LIST OF SCHEMES…………………………………………………………….........……xii CHAPTER I General Introduction of Bacteriochlorins Bacteriochlorophylls and Bacteriochlorins………………………………………......1 Synthesis of Bacteriochlorins………………………………………………………...9 Summary and Overview……………………………………………………………..17 References……………………………………………………………………………20 CHAPTER II Synthesis and Photophysical Characteristics of 2,3,12,13- Tetraalkylbacteriochlorins Introduction………………………………………………………………………….27 Results and Discussion………………………………………………………………31 (1) Synthesis…………………………………………………………………31 (2) Photophysical Characterization………………………………………….44 Conclusion………………………………………………………………………...…55 Experimental Section…………………………………………………………….…..56 Reference...……………………………………………………………………....…..70 CHAPTER III Synthetic Approaches Towards Unsymmetrically Substituted Bacteriochlorins Introduction……………………………………………………………............…….75 v Result…………………………………………………………………......………….81 (1) Retrosynthesis Analysis……………………………………….........……81 (2) Synthesis of Hydrodipyrrins………………………………………..........83 (3) Exploration of Bacteriochlorin Formation…………………………........87 (4) Characterization………………………………………………….......…..97 Discussion………………………………………………………………….......….104 (1) Joining of the Eastern Half and the Western Half ……………............104 (2) Ring Closure…………………………………………………...........…..106 (3) Leaving Group and Methylthio shift……………………………............109 Conclusion………………………………………………………………….............111 Experimental Section……………………………………………………............….113 Reference…………………………………………………………………...............131 CHAPTER IV Construction of the Bacteriochlorin Macrocycle with Concomitant Nazarov Cyclization to Form the Annulated Isocyclic Ring – Analogues of Bacteriochlorophyll a Introduction………………………………………………………………...........….136 Results………………………………………………………………………............141 (1) Reconnaissance…………………………………………………............141 (2) Synthesis…………………………………………………......................145 (3) Characterization…………………………………………………...........157 Discussion………………………………………………….....................................163 (1) Installation of the Isocyclic Ring………………………….................…163 (2) Features of the Nazarov Cyclization………………………................…165 (3) Comparison of Routes…………………………………….................…166 (4) Synthetic Attributes…………………………………….................……168 vi Experimental Section……………………………………………….................…..171 References……….………………………………………………….......................188 vii LIST OF TABLES Table 2.1. Acid survey for the self-condensation of dihydrodipyrrin carboxaldehydes...39 Table 2.2. Spectral characteristics of bacteriochlorins in toluene ....................................47 Table 2.3. Photophysical properties of bacteriochlorins...................................................52 Table 3.1. Survey of conditions to prepare bacteriochlorin In-BC-1...............................88 Table 3.2. Spectral properties of bacteriochlorins..........................................................103 Table 4.1. Conditions for bacteriochlorin (BC-T) formation from 12-T ......................154 Table 4.2. Investigation of the scope of bacteriochlorin formation..............................156 Table 4.3. Spectral characteristics of bacteriochlorins .................................................162 viii LIST OF FIGURES Figure 1.1. Pigments of life................................................................................................2 Figure 1.2. Absorption spectra of magnesium octaethylporphyrin (blue line), chlorophyll a (green) and b (dashed green), and bacteriochlorophyll a (red)....................3 Figure 1.3. Structures of natural bacteriochlorophylls......................................................5 Figure 1.4. Natural hydroporphyrins with geminal dialkyl motif ...................................6 Figure 1.5. Core structure of synthetic bacteriochlorins...................................................7 Figure 1.6. Typical derivatives of BChl a. .......................................................................10 Figure 1.7. Symmetrically and unsymmetrically substituted bacteriochlorin .................19 Figure 2.1. Natural bacteriochlorophylls .........................................................................28 Figure 2.2. Progression of structural complexity along the path to a free base derivative of BChl a.............................................................................................................31 Figure 2.3. Dihydrodipyrrins used in chlorin syntheses. ..................................................34 Figure 2.4. ORTEP drawing of BC-MM. Ellipsoids are at the 50% probability level and hydrogen atoms (except N–H) are omitted for clarity...................................42 Figure 2.5. New and benchmark bacteriochlorins. ...........................................................45 Figure 2.6. Absorption (solid) and fluorescence (dashed) spectra of bacteriochlorins in toluene............................................................................................................46 Figure 2.7. Low- and mid-frequency regions of the Qy-excitation RR spectra of CuBC0 (ex = 730 nm; CH2Cl2 solution) and CuBC-MM (ex = 737 nm; benzene solution)..........................................................................................................50 Figure 2.8. Integrated intensity of Qy absorption manifold [Qy(0,0) and Qy(1,0)] versus that of the total spectrum (300–900 nm) when plotted in wavenumbers (vertical axis) versus the radiative rate constant kf obtained from the s and f ix values (x-axis). The overall linear relationship reflects the consistency of the measurements and analysis.............................................................................55 Figure 3.1. Hydrodipyrrins for studies of bacteriochlorin formation ..............................82 Figure 3.2. Absorption spectrum of TDC-1 (top) and Ni-TDC-2 (bottom)