Making Lasting Bonds Through Synthetic Chemistry

1. Making Lasting Bonds Through Synthetic Chemistry Tim Hubin and William Kelly Southwestern Oklahoma State University

2. Overview • Laboratory Work • Multistep Organic Synthesis and Characterization of a Macrocyclic Ligand (unique to each group) • Complexation with a Transition Metal Ion (unique to each individual) • Physical and Chemical Characterization of the Metal Complex • Off-Site Screening by Collaborators for Biological/Catalytic Applications • Classroom Work • Principles of Organic Chemistry supporting the ligand syntheses • Principles of Inorganic Chemistry supporting the coordination chemistry of transition metal complexes • Principles of Physics and Analytical Chemistry supporting the physical and chemical characterization of the ligands and metal complexes • Supporting lectures on the Biological and Catalytic Applications of Complexes • Communication of Scientific Product • Poster Presentation during final day(s) of program • Written manuscript in a journal format (expect actual publication of student work combined into appropriate groups of related compounds)

3. Synthetic Scheme

4. Applications of Bridged Azamacrocycles • Catalysts for Oxidation Reactions (collaborator Yin in China) • Anti-HIV and Anti-Cancer Activity through CXCR4 Receptor Binding

5. Blocking CXCR4 receptor functions CXCL12/HIV Drug Cell

6. CXCR4 and Cancer Cell Metastasis - CXCL12 is normally responsible for trafficking of lymphocytes - CXCL12 is secreted by stromal, lung and liver cells, and lymph nodes - The interaction at the cell membrane is through CXCR4, which is over-expressed in some cancers - Potential mechanism of metastasis Normal cell Cancer cell

7. Introduction An Improved MRI Contrast Agent? Why Cobalt?There is an abundance of information on cobalt complexes, so comparisons can be made with similar complexes. Ligand Synthesis: Complex Synthesis Conclusions Characterization of the Complex Acknowledgements The Synthesis and Characterization of Co(AcBcyclam)PF6Jonas Lichty and Timothy J. Hubin. Dept. of Chemistry, Southwestern Oklahoma State University MassSpectrum IR Spectrum -Modulate magnetic properties of water -Utilize Gd3+ because of its high magnetic moment as a result of its seven unpaired electrons -The more open coordination sites available to interact with water, the better the resolution -Complex must be stable, because Gd3+ is toxic to humans -Gd3+ is 9 – coordinate, ligand is octadentate, so only one site is available to interact with water -Ethylene cross – bridge makes it more “rigid”, which makes the complex more stable -The ligand field strength (avg strength of metal-donor bonds) of this cross – bridged ligand is comparable to similar ligands without cross – bridges -The ligand leaves two more open coordination sites on Gd3+ Elemental Analysis UV-Vis Spectrum Overall Yield 56% for four steps. Purity confirmed by Elemental Analysis to 0.4% CHN. Identity confirmed by NMR comparison to literature. The energy of the lowest energy absorption band can be used to estimate the ligand field strengths of the ligands in the complexes.- This has been calculated for the complex and for cis – [CoL2]+[CO3]-. The results were nearly identical. (both strong field ligands) -This similarity means that the addition of the cross bridge has not affected the ligand field strength, even though it made the ligand more rigid. Overall Yield 63% for three steps. Purity confirmed by Elemental Analysis to 0.4% CHN. Identity confirmed by NMR comparison to ligand NMR Data Crystal Structure [Also need Magnetic Moment and Conductance] -The synthesized Co3+ complex of 4, 11 – diacetato – 1, 4, 8, 11 – tetraazabicyclo[6,6,2]hexadecane was pure. -From the UV-Vis we can conclude that AcBcyclam is a strong field ligand -NMR, Mass Spec, and IR have all been assigned -Cobalt is the first metal put into this ligand that gives an NMR (diamagnetic) -X – ray crystal structure confirms predicted geometry -Dr. Tim Hubin --Dr. David VanderVelde, of the University of Kansas -Dr. Steven Archibald, of the University of Hull (U.K.)

8. Course Evaluations by Students (n = 33)

9. Student Evaluation Comments • “This has been the best lab I have ever been in…I really liked how the lab was one long experiment.” • “I really found this course to be a great exposure to synthetic chemistry. I have learned many useful skills that I will continue to use.” • “This lab has been great. It feels like I am accomplishing a lot more. I am learning how to prepare a journal article. It has been a very good experience.” • “I have enjoyed the way the lab is set up. Lab feels like I am accomplishing something instead of just doing an experiment and throwing it away.” • “The lab portion of the course was a very helpful mini research experience.” • “I love Inorganic Chemistry Lab. Sometimes it is tough, but everything is interesting. We have fun in lab and learn a lot…” • “Great lab. Required application of knowledge and skills while expanding on both.” • “Excellent teaching, fantastic techniques, and clear, concise work meaningful & relevant to subject.” • “This lab made me enjoy Inorganic. It actually made me like Chem. Labs again.” • “This lab required a lot of effort. Dr. Hubin is a very nice instructor but the course work is really tough.”

10. Publishable Work? SPRING 2006 • “Dichloro(4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane)iron(III) hexafluorophosphate” McClain, J. M.; Maples, D. L.; Maples, R. D.; Matz, D. L.; Harris, S. M.; Nelson, A. D.-L.; Silversides, J. D.; Archibald, S. J.; Hubin, T. J. ActaCryst. C, 2006, C62, m553. • “Synthesis and Characterization of the chromium(III) complexes of ethylene cross-bridged cyclam and cyclen ligands” Maples, D. L.; Maples, R. D.; Hoffert, W. A.; Parsell, T. H.; van Asselt, A.; Silversides, J. D.; Archibald, S. J.; Hubin, T. J. Inorg. Chim. Acta2009, 362, 2084-2088. FALL 2007 (In Preparation) • “Chloro(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)copper(II) chloride” • “Dibromo(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)cobalt(III) hexafluorophosphate” Fall 2009 (In Preparation) • “Dichloro(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)cobalt(III) hexafluorophosphate” Fall 2011 (in Preparation) • “1,8-Dimethylcyclam complexes of manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II)” Fall 2013 (in Preparation) • “Transition Metal Complexes of Dibenzyl Tetraazamacrocycles”