SYNTHETIC STUDIES OF Re(CO)3 BIOCONJUGATES, AZADIPYRROMETHENES, AND FERROCENE-MODIFIED COMPOUNDS A Dissertation Presented to The Graduate Faculty at The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Kullapa Chanawanno December, 2016 SYNTHETIC STUDIES OF Re(CO)3 BIOCONJUGATES, AZADIPYRROMETHENES, AND FERROCENE-MODIFIED COMPOUNDS Kullapa Chanawanno Dissertation Approved: Accepted: ___________________________ ___________________________ Advisor Department Chair Dr. Christopher J. Ziegler Dr. Christopher J. Ziegler ___________________________ ___________________________ Committee Member Dean of the College Dr. Claire A. Tessier Dr. John C. Green ___________________________ ___________________________ Committee Member Dean of the Graduate School Dr. Sailaja Paruchuri Dr. Chand K. Midha ___________________________ ___________________________ Committee Member Date Dr. Wiley J. Youngs ___________________________ Committee Member Dr. Thein Kyu ii ABSTRACT + The rhenium tricarbonyl (Re(CO)3 ) is one of the most commonly used organometallic cores for labeling various molecular types. The direct labeling of Re(I) via imine formation by the use of pyridine-2-carboxaldehyde (pyca) was achieved by + coordination to the fac-[Re(CO)3] . The Re(CO)3-aldehyde adduct reacts with a variety of aromatic/aliphatic amines and peptides resulting in Re(CO)3-conjugates. In the second chapter, this thesis presents a study on Re(CO)3 pyridine–imine complexes with pendant phenol groups. The effects of the position of the hydroxyl group (para, meta or ortho to the imine) were investigated. These compounds exhibit pH- dependent metal-to-ligand charge transfer bands. A series of Re(CO)3-imine with ferrocenyl units was presented in the third chapter. Hydrazine can be used as a linker to connect ferrocene and Re(CO)3, resulting in 1:1, 2:1, and 1:2 ferrocene:Re(CO)3 complexes. The electrochemistry and spectroscopy of the compounds were investigated and DFT and TDDFT calculations provided insight electronic structures of the conjugates. In the fourth chapter, this thesis presents a Re(CO)3-modified lysine that can iii be generated in a one-pot reaction. This Re(CO)3-modified lysine can be incorporated into four different peptides using solid phase peptide synthesis. And cellular uptake was monitored via the use of a fluorescein modified variant. The number of studies of azadipyrromethenes (ADPM) and their BF2 complexes (aza-BODIPY) has been growing due to their long-wavelength absorptions and high emissions observed in these compounds. Additionally, the discovery of the related novel fluorophore, BOPHY, by Ziegler’s group in 2014 has also initiated numerous studies focusing on the development of these compounds. In the next chapter, this thesis presents a study of structures and photophysical of ADPMs and several aza-BODIPYs. Both ADPMs and aza-BODIPYs are fluorescent, and the aza-BODIPYs exhibit red shifted emissions relative to their ADPMs analogs. In the subsequent chapter, the synthesis and characterization of the first ADPM and aza- BODIPY complexes with ferrocene directly connected to the α-pyrrolic carbon is reported. The ferrocene units are electronically coupled to each other. DFT and TDDFT calculations are in agreement with the experimental data. In the last experimental chapter, the first organometallic BOPHY substituted with two ferrocene units is reported. The study revealed an unprecedented long-range metal-metal coupling between the ferrocene-centered oxidation waves. iv ACKNOWLEDGEMENTS I would like to sincerely thank Dr. Christopher Ziegler, my great Ph.D. advisor and mentor. No words can honestly express my appreciation and describe how lucky I am to be one of his student. He provided support, understanding, and freedom for me to continue several projects, as well as the patience that he has, encourage me to be the chemist I am today. I would also like to extend my gratitude to Dr. Richard Herrick from College of Holy Cross, Worcester, MA, who always has an insightful answer to my questions and he promptly guides me when I am in doubt. I would also like to thank the members of my Ph.D. committee: Dr. Claire Tessier, Dr. Wiley Youngs, Dr. Sailaja Paruchuri and Dr. Thein Kyu for their time and helpful advice. My acknowledgement goes to the UA department of Chemistry for not only accepting me into the program, but also financially supporting me during my Ph.D. career through teaching assistantship. I gratefully acknowledge the Royal Thai Government for the financial support throughout my study. I would also like to thank Dr. Victor Nemykin, University of Minnesota at Duluth, Dr. Sailaja Paruchuri and Dr. Thomas Leeper, University of Akron, for their kind help and collaborations. v Friendship and support are those two things you wish for the most when being 9,000 miles away from home on a Ph.D. journey. Thank you Dr. Sasiwimon (Dao) foryour love and unconditional support. To Diane and Dr. Lakshman Negi, Diane Walter, and Charles ‘grandpa’ Ashley: I am very thankful for all your friendship and help during my ups and downs. I had some not-so-great years and I cannot imagine going through those without you. To all my labmates: Ingrid, Laura, Abed, Allen, you are my good friends. These people are the best lab crew you could ask for. All of you make me love working in this lab. Lastly, I would like to thank my family: my grandfather Somkid, my uncles Meta, Metee, as well as Peter Chant who came to help me get set up during the first week in the US, and my aunts Huan and Aood. Thank you for believing in this kid. vi TABLE OF CONTENTS Page LIST OF TABLES ........................................................................................................ xi LIST OF FIGURES ................................................................................................... xiii LIST OF SCHEMES................................................................................................... xix LIST OF ABBREVIATIONS .................................................................................... xxii CHAPTER I. INTRODUCTION AND BACKGROUND ............................................................... 1 1.1 Coordination Chemistry of Re(I) Carbonyl Complexes ...................................... 1 + The Rhenium Tricarbonyl Core (Re(CO)3 )........................................................... 1 Pyridine-2-Carboxaldehyde Ligand Systems ......................................................... 5 Re(CO)3 Complexes with Biologically Relevant Pyca-diimine Ligands ............. 10 Re(CO)3 Complexes with Non-Biologically Relevant Pyca-diimine Ligands ..... 16 Optical properties of Re(CO)3 with Pyca-diimine Phonolic Ligands................... 19 Re(CO)3-ferrocene Schiff base complexes ........................................................... 23 + 1.2 Re(CO)3 Peptide Conjugates ............................................................................ 26 Metal-peptide Conjugates ..................................................................................... 26 Solid Phase Peptide Synthesis (SPPS) and Metal Precursor for SPPS................. 27 vii Rhenium Metal-Peptide Conjugates and Single Amino Acid Chelator (SAAC) ................................................................................................................. 33 1.3 aza-BODIPY and BOPHY dyes ......................................................................... 45 Fluorescence ......................................................................................................... 45 Organic Fluorophores ........................................................................................... 48 Azadipyrromethene .............................................................................................. 49 BOPHY dyes ........................................................................................................ 61 II. THE SYNTHESIS AND pH-DEPENDENT BEHAVIOUR OF Re(CO)3 CONJUGATES WITH DIIMINE PHENOLIC LIGANDS ........................................ 71 Introduction .............................................................................................................. 71 Experimental ............................................................................................................ 73 Results and discussion .............................................................................................. 85 Conclusions .............................................................................................................. 93 III. USING HYDRAZINE TO LINK FERROCENE WITH Re(CO)3: A MODULAR APPROACH ....................................................................................... 94 Introduction .............................................................................................................. 94 Experimental ............................................................................................................ 96 Results and discussion ............................................................................................ 109 Conclusions ............................................................................................................ 121 IV. FACILE RHENIUM–PEPTIDE CONJUGATE SYNTHESIS USING A ONE-POT DERIVED Re(CO)3 REAGENT ............................................................. 122 Introduction ............................................................................................................ 122 Experimental .........................................................................................................