Topics in Molecular Topology Tim Hubin Department of Chemistry and Physics Southwestern Oklahoma State University Educational and Biographical Information Biographical Educational – Hometown: Hanston, Kansas (pop. 350) – Wife: Becki – Kids: David (5), Daniel (3) – – – – 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 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 NH2 NH NH3 NH HN NH HN HN NH HN NH HN NH2 HN HN NH2 H2N – Connectedness of individual molecules in supramolecular systems 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 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 O O 18-Crown-6 + O K 15-Crown-5 O O O + O O K O O O – Geometry: metal ions gain stability from particular geometries d6 Octahedral 3+ Co d8 Square Planar 2+ Pd – Electronics: hard-soft acid-base theory Hard = small, not polarizable Fe3+---O2- Soft = large, polarizable Hg2+---S2- Complementarity and Binding Affinity Binding Affinity Electronics Geometry Size Complementarity 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 NH2 NH NH3 NH2 NH2 NH HN NH HN HN NH HN NH HN HN HN H2N Increasing Topological Constraint and Complex Stability – Rigidity: inflexibility or fixedness of donor atoms in a ligand H2N NH2 N N N N Increasing Rigidity and Complex Stability Constraint and Binding Affinity Rigidity Binding Affinity Topology Electronics Size Geometry Complementarity Constraint Our Approach to Exploiting Topology and Rigidity O n NH HN O H H CH3CN NH HN N N H H n N RX n = 0 or 1 independently RX = MeI or BnBr CH3CN N n n cyclam N N+ R H H n n R N+ N NaBH4 2X - N N N N R 95% EtOH if R = Bn Pd/C, H2 n N HN HOAc NH N R n n Weisman et al. J. Am. Chem. Soc. 1990, 112, 8604. Weisman et al. J. Chem. Soc., Chem. Commun. 1996, 947. n Metal Complexes Co(Me2B12N4)Cl2 [Ni(Me2B14N4)(acac)]+ Fe(Bn2B12N4)Cl2 Application #1 Aqueous Oxidation Catalysis Problem: Catalyst Decomposition – Transition Metal Complexes decompose in H+ or OH» Acidic Conditions » Basic Conditions R3N R3N » Oxygenated Conditions Kinetic Metal CuII M M R3N H+ OH- M R3NH+ R3N O2/H2O + + M M(OH)n R3N + Stability of Our Complexes: 1 M HClO4 Ligand Me2B14N4Me6 Me2B14N4 Me2B13N4 Me2B12N4 t1/2 > 8 yr > 6 yr >8 yr 30 h Metal CuII Ligand Me414N4 cis-14N4Me6 trans-14N4Me6 t1/2 2s 2s 22 d MxOy Electrochemical Studies Ligands stabilize metals in multiple oxidation states Cyclic Voltammetry of Me2B14N4 Complexes CuII NiII Mn(Me2B14N4)Cl2 identified as active catalyst CoII catalyst H2O2 FeII Patents: US 6,218,351 US 6,387,862 US 6,608,015 MnII 2 1.5 1 0.5 0 -0.5 Potential (V) vs SHE -1 -1.5 -2 -2.5 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 O O O O DOTA O N N N N O O O Gd-DOTA NO O O OH2 Gd O O N O O N N O – 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 O with water O Result: stable complex with CH 3 N O NH HNN N2 N roughly twice the relaxivity N N OH OH Gd OH2 of Gd-DOTA N HO OH N N NH HN O L ON 2 N CH3 O L N Patent: US 6,656,450 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 NH HN NH HN NH NH N N NH HN HN Zn N 2+ NH HN – Metal binds to CXCR4 co-receptor of the immune cells through aspartate residues Bridger, et. al. J. Biol. Chem. 2001, 276, 14153. − Recent studies suggest cis-binding of the aspartate residues, requiring folded ligand Sadler, et. al. J. Am. Chem. Soc. 2002, 124, 9105. 2+ Zn N HN Current progress Cross-bridged bis-tetraazamacrocycles – Cross-bridge dictates cis-folded structure thought needed – Goal is stronger and more selective binding to CXCR4 coreceptor CH3 N N H3C N N N N N N N N Zn N N L L N N Zn N L R N L R – Ligand, Cu2+, and Zn2+ complexes synthesized – Meta-xylyl linked analogue and complexes synthesized – Currently undergoing initial anti-HIV screening 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 H O O R R O H O – p-p interactions H N N – Metal-Ligand interactions H Zn H N N H Mechanical Bonds Physical interlocking of molecules – May be no covalent or even non-covalent interactions – Fairly recently exploited types of supramolecular systems Catenane RotaxaneNH NH2 Template Knot 2+ NH NiCl2 H2O NH2 O O H H Reactions: using aNHnon-covalent interaction H O to NH NH NH organize a molecule for covalent bond formation NH NH2 NH2 2+ NH NiCl2 H2O 2 2 2+ NH Ni NH2 Ni NH NH2 O O H H 2+ NH H2O 2 N Ni NH N NaBH4 H2O NH HN Ni NH HN Barefield, et. al. Inorganic Synthesis, 1976, 16, 220. CNH2O NH HN NH HN cyclam Templates for Mechanical Bonds + N O HO O + N Br HO O O Br J. F. Stoddart J. P. Sauvage 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. Application #2 Molecular Weaving Molecular Weaving (Hubin): multiple molecular strands mechanically interlocked by multiple crossovers Hubin and Busch, Coord. Chem. Rev. 2000, 200-202, 5. 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 Proposed Weaving Ligands N N N N N N N N N (b) (a) N N N NN N N N O N N H N N N N N N N H O (d) (c) (d) N N N H O (c) N Ligand Synthesis O HO H3 C N O SeO2, py, H2 O MeO N N MeOH, H2SO4 N N N OH CH3 OMe O O O O MeO H2N N N N H N N N N MeOH N H OMe O N O Evidence of the Desired Geometry [{CoL2}CoCl4{CoL2}] Acknowledgments Oxidation Catalysis Prof. Daryle Busch 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 Anti-HIV: Prof. Steve Archibald Robert Ullom Joe Blas Taulyn Snell McPherson College Stine Research Fund Divergent Molecular Turn Tim Hubin Molecular David Cockriel Weaving Robert Ullom Society of Self Fellows, Univ. of Kansas ACS Petroleum Research Fund