Halogen-Bonding Catalysis George Neuhaus Prof. Orion B. Berryman’s Lab April 11, 2014 UMCUR 1

Berryman Lab  Supra-molecular chemistry  Ion recognition  Gene expression control  Halogen-bonding organocatalysis 2

Catalysts’ Role in Medicinal Chemistry  Catalysts promote chemical reactions  Inorganic catalysts  Organocatalysts  Pharmaceutical production  Guanidine synthesis 1  Michael-type addition Katritzky, A. R. and Rogovoy, B. V Recent developments in guanylating agents. ARKIVOC iv, Taylor, M. S. and Jacobsen, E. N., Asymmetric Catalysis by Chiral Hydrogen-Bond Donors. Angewandte Chemie, International Edition 45,

Pharmaceutical Production  Guanidine Synthesis 3  Michael-type Addition 4 Cimetidine Zanamivir (+)-Tanikolide Zemplar 4 3. Otero, A., Guanidines: from classical approaches to efficient catalytic syntheses. Royal Society of Chemistry, DOI: /c4cs00013g 4. Maltsev, O. V., Beletskaya, I. P., Zlotin, S. G., Organocatalytic Michael and Friedel-Crafts reactions in enantioselective synthesis of biologically active compunds. Rus. Chem. Rev. 80,

Halogen-bonding  Non-covalent attractive interaction 5  Due to formation of the sigma-hole  Requirements 5  Linearity  Specific bond length EWG Halogen Lewis Base Sigma-hole 5 5. Metrangolo, P., Meyer, F., Pilati, T., Resnati, G. and Terraneo, G., Halogen Bonding in Supramolecular Chemistry. Angewandte Chemie, International Edition 47,

Catalyst Design  Designed to bind with carbonyl functionality  Bidentate halogen-bonds  Lower transition state energy  Activate substrates by removing electron density °

Catalyst Design Terphenyl Scaffold Tert-butyl groups Iodinated imidazolium 7

Catalyst Design 1 8

NMR Studies  Nuclear Magnetic Resonance Spectroscopy  Each compound has a unique spectrum  Depends on the magnetic environment surrounding the protons CHCl 3 A B C D E F G H 9

NMR Studies  NMR titrations  Add small amounts of a different molecule to the sample  Take an NMR after each addition  The proton peaks will shift  Analyze how far the peaks shift  Learn about structure  Learn the strength of the interaction 10

NMR Studies eq. of TBABr 1.0 eq. of TBABr 5.0 eq. of TBABr

Future Studies  Screening reactions involved in pharmaceutical production  Michael type addition reaction  Guanidine synthesis 12

Conclusion  Design, synthesize, and test halogen-bonding organocatalysts  Improve the way pharmaceuticals are produced  Improving synthesis for current drugs  Open new reaction pathways to a wider veriety of drugs 13

A special thanks  Funding  Watkins Scholarship endowment  Davidson Honors College  University of Montana  Chemistry Department  Center for Biomolecular Structure and Dynamics  College of Humanity and Sciences  Vice President of Research  Support  Prof. Orion B. Berryman and the Lab Crew  Casey Massena 14