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

2. Educational and Biographical Information
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
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

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: Ni 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
Hard = small, not polarizable Fe3+---O2-
Soft = large, polarizable Hg2+---S2-

6. Complementarity and 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. 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
R3N M +
R3NH+ M H
R3N M OH -
R3N M(OH)n O /H
R3N MxOy 2
R3N M
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,
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
Barefield, et. al. Inorganic Synthesis, 1976, 16, 220.
cyclam

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, , 5.

21. Proposed Weaving Ligands
(c)
(d)

22. Ligand Synthesis

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

24. Acknowledgments Anti-HIV: Prof. Steve Archibald
Oxidation Prof. 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
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