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Topics in Molecular Topology

Topics in Molecular Topology. Tim Hubin Department of Chemistry and Physics Southwestern Oklahoma State University. Biographical Hometown: Hanston, Kansas (pop. 350) Wife: Becki Kids: David (5), Daniel (3). Educational B.S. Education—KSU 1994 B.S. Chemistry—KSU 1994

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Topics in Molecular Topology

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  1. Topics in Molecular Topology Tim Hubin Department of Chemistry and Physics Southwestern Oklahoma State University

  2. Biographical Hometown: Hanston, Kansas (pop. 350) Wife: Becki Kids: David (5), Daniel (3) Educational B.S. Education—KSU 1994 B.S. Chemistry—KSU 1994 Ph.D. Chemistry—KU 1999 Postdoc—Caltech 1999-2000 Professional McPherson College 2000— Courses Taught General Chemistry College Chemistry II Organic Chemistry I and II General Physical Chemistry Inorganic Chemistry I and II Biochemistry Educational and Biographical Information

  3. Introduction • Topology: the study of the properties of geometric configurations… (American Heritage Dictionary) • Molecular Topology: (Daryle Busch/Tim Hubin) • Connectedness of donor atoms in a ligand • Connectedness of individual molecules in supramolecular systems

  4. Coordination Chemistry • Coordination Compound = new chemical compounds formed by the binding of simpler, yet distinct, molecules by non-covalent bonds • Ligand = atom, ion, or molecule that can donate a pair of electrons to a metal ion :C≡O: H2Ö: R3P: • Simple Covalent Bond = formed by the sharing of one electron from each atom H3C• + •H H3C—H • Coordinate Bond = formed by the donation of both electrons from one atom H3N: + Ni2+ H3N—Ni2+ Ligand Metal Complex

  5. Enhancing Metal-Ligand Binding Affinity • Complementarity: match between metal and ligand (minimum for strong binding) • Size: metal ion fits the ligand allowing optimum bond lengths • Geometry: metal ions gain stability from particular geometries • Electronics: hard-soft acid-base theory Soft = large, polarizable Hg2+---S2- Hard = small, not polarizable Fe3+---O2-

  6. Complementarity and Binding Affinity Binding Affinity Electronics Geometry Size Complementarity

  7. Increasing Binding Affinity Even More • Constraint: factors reducing freedom in ligand systems and leading to optimization of binding affinity • Topology: connectedness of donor atoms in a ligand • Rigidity: inflexibility or fixedness of donor atoms in a ligand Increasing Topological Constraint and Complex Stability Increasing Rigidity and Complex Stability

  8. Constraint and Binding Affinity Rigidity Binding Affinity Topology Electronics Geometry Size Complementarity Constraint

  9. Our Approach to Exploiting Topology and Rigidity cyclam Weisman et al. J. Am. Chem. Soc.1990, 112, 8604. Weisman et al. J. Chem. Soc., Chem. Commun.1996, 947.

  10. Metal Complexes Co(Me2B12N4)Cl2 [Ni(Me2B14N4)(acac)]+ Fe(Bn2B12N4)Cl2

  11. + R3N M R3NH+ + M - OH R3N + M(OH)n R3N M O /H O 2 2 R3N M R3N + MxOy Application #1 Aqueous Oxidation Catalysis • Problem: Catalyst Decomposition • Transition Metal Complexes decompose in H+ or OH- • Acidic Conditions • Basic Conditions • Oxygenated Conditions • Kinetic Stability of Our Complexes: 1 M HClO4 H Metal Ligand t1/2 CuII Me2B14N4Me6 > 8 yr Me2B14N4 > 6 yr Me2B13N4 >8 yr Me2B12N4 30 h Metal Ligand t1/2 CuII Me414N4 2 s cis-14N4Me6 2 s trans-14N4Me6 22 d

  12. Electrochemical Studies • Ligands stabilize metals in multiple oxidation states • Mn(Me2B14N4)Cl2 identified as active catalyst Cyclic Voltammetry of Me2B14N4 Complexes CuII NiII CoII FeII Patents: US 6,218,351 US 6,387,862 US 6,608,015 MnII Potential (V) vs SHE

  13. Application #2 MRI Contrast Agents • Paramagnetic metal complexes (usually Gd3+) used to modify relaxivity of water protons in tissue giving contrasted images • Complex must be stable, because Gd3+ is toxic to humans • Gd3+ is 9–coordinate, ligand is octadentate, only one site can interact with H2O • Relaxivity (contrast) should improve with more open sites available to interact with water DOTA Gd-DOTA Result: stable complex with roughly twice the relaxivity of Gd-DOTA Patent: US 6,656,450

  14. Application #3 Anti-HIV Drugs • Background • “Bis-” or linked-tetraazamacrocycles exhibit activity against HIV • AMD3100 and its Cu and Zn complexes are in clinical trials • Metal binds to CXCR4 co-receptor of the immune cells through aspartate residues • Recent studies suggest cis-binding of the aspartate residues, requiring folded ligand Bridger, et. al. J. Biol. Chem.2001, 276, 14153. Sadler, et. al. J. Am. Chem. Soc.2002, 124, 9105.

  15. Current progress • Cross-bridged bis-tetraazamacrocycles • Cross-bridge dictates cis-folded structure thought needed • Goal is stronger and more selective binding to CXCR4 coreceptor • Ligand, Cu2+, and Zn2+ complexes synthesized • Meta-xylyl linked analogue and complexes synthesized • Currently undergoing initial anti-HIV screening

  16. New Supramolecular Topologies • Supramolecular Chemistry: interactions of molecules through non-covalent bonds • Individual molecules are still recognizable • Some interaction imposes a degree of organization • Types of non-covalent interactions • Hydrogen bonding • p-p interactions • Metal-Ligand interactions

  17. Mechanical Bonds • Physical interlocking of molecules • May be no covalent or even non-covalent interactions • Fairly recently exploited types of supramolecular systems • Template Reactions: using a non-covalent interaction to organize a molecule for covalent bond formation Catenane Rotaxane Knot cyclam Barefield, et. al. Inorganic Synthesis, 1976, 16, 220.

  18. Templates for Mechanical Bonds J. F. Stoddart J. P. Sauvage

  19. Application #1 Divergent Molecular Turns • Types of Molecular Turns • New Mechanically Bonded Molecules are possible A “Rotaxaknot” Hubin, et. al. Adv. in Supramolec. Chem.,1999, 5, 1.

  20. Application #2 Molecular Weaving • Molecular Weaving (Hubin): multiple molecular strands mechanically interlocked by multiple crossovers • Perceived Requirements • Rigid constraint of adjacent binding sites to opposite sides of the ligand strand • Strong metal complexes utilizing kinetically labile metals • Spacer unit between binding sites providing sufficient space for the metal ion Hubin and Busch, Coord. Chem. Rev.2000, 200-202, 5.

  21. Proposed Weaving Ligands (d) (c)

  22. Ligand Synthesis

  23. Evidence of the Desired Geometry [{CoL2}CoCl4{CoL2}]

  24. Acknowledgments Anti-HIV: Prof. Steve Archibald Robert Ullom Joe Blas Taulyn Snell McPherson College Stine Research Fund Divergent Tim Hubin Molecular Turn Molecular David Cockriel Weaving Robert Ullom Society of Self Fellows, Univ. of Kansas ACS Petroleum Research Fund OxidationProf. Daryle Busch Catalysis Prof. Steve Archibald Prof. Alan van Asselt Wes Hoffert Trenton Parsell Procter & Gamble McPherson College Stine Research Fund MRI Contrast:Prof. Tom Meade Jonas Lichty Shawn Allen Adedamola Grillo National Institutes of Health McPherson College Stine Research Fund

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