topics in molecular topology tim hubin department of chemistry and physics southwestern oklahoma...
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Topics in Molecular Topology
Tim Hubin
Department of Chemistry and Physics
Southwestern Oklahoma State University
Educational and Biographical Information 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
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
NH
NH HN
HN
NH3
NH2
NH HN
H2NNH
NH HN
HN
HN
HNNH2
NH2
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
– Geometry: metal ions gain stability from particular geometries
– Electronics: hard-soft acid-base theory
O
OO
OOO
O
O
O
O
O
K+
K+
18-Crown-6 15-Crown-5
Hard = small, not polarizable Fe3+---O2- Soft = large, polarizable Hg2+---S2-
Co3+ Pd
2+
d6 Octahedral d8 Square Planar
BindingAffinity
Size
Geometry
Electronics
Complementarity and Binding Affinity
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
– Rigidity: inflexibility or fixedness of donor atoms in a ligand
NH
NH HN
HN
NH3
NH2
NH HN
H2NNH
NH HN
HN
HN
HNNH2
NH2
Increasing Topological Constraint and Complex Stability
H2N NH2 NN N N
Increasing Rigidity and Complex Stability
Constraint and Binding Affinity
BindingAffinity
Complementarity Constraint
Size Geometry
Electronics
Topology
Rigidity
Our Approach to Exploiting Topology and Rigidity
Weisman et al. J. Am. Chem. Soc. 1990, 112, 8604.Weisman et al. J. Chem. Soc., Chem. Commun. 1996, 947.
N
NN
N
H
H
N+
N N+
N
R
R H
H
N
N N
N
R
R
RX
CH3CN
95% EtOH
NaBH4
HN
HNNH
NHCH3CN
O
HH
O
2 X -
n
n
n
n
n
n
n
n
n = 0 or 1 independentlyRX = MeI or BnBr
HOAc
Pd/C, H2
if R = Bn
NH
N HN
N
n
n
cyclam
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
» Oxygenated Conditions
Kinetic Stability of Our Complexes: 1 M HClO4
R3N MOH-
R3N + M(OH)n
HR3N M+
R3NH+ + M
O /H OR3N + MxOy
2 2R3N M
Metal Ligand t1/2
CuII Me2B14N4Me6 > 8 yrMe2B14N4 > 6 yrMe2B13N4 >8 yrMe2B12N4 30 h
Metal Ligand t1/2
CuII Me414N4 2 s cis-14N4Me6 2 s trans-14N4Me6 22 d
Electrochemical Studies Ligands stabilize metals in
multiple oxidation states
Mn(Me2B14N4)Cl2 identified as active catalyst
-2.5-2-1.5-1-0.500.511.52
Cyclic Voltammetry of Me2B14N4 Complexes
CuII
NiII
CoII
FeII
MnII
Potential (V) vs SHE
H2O2
catalyst
Patents: US 6,218,351US 6,387,862US 6,608,015
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
O
O
N
N
N
GdO
ON
O
O
OH2O
O
NN
N N
O
O
O O
O
O
OO
DOTAGd-DOTA
N
N
N
Gd
O
ON
O
O
OH2
OH2
OH2
Result: stable complex with roughly twice the relaxivityof Gd-DOTA
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
– 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
NH N
NH NHNHN
NHNHNH N
NHNHN
NHNH
NH
Zn2+
Zn2+
Bridger, et. al. J. Biol. Chem. 2001, 276, 14153.
Sadler, et. al. J. Am. Chem. Soc. 2002, 124, 9105.
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
N N
N NNN
NN
CH3
CH3N
Zn
N L
N
N
R
L N
Zn
NL
N
N
R
L
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
– interactions
– Metal-Ligand interactions
RO
O HR
O
OH
Zn
N N
N N
H
H
H
H
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
cyclamBarefield, et. al. Inorganic Synthesis, 1976, 16, 220.
Templates for Mechanical Bonds
O
O
OOH
O
OH
Br
N+
N+
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
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.
Proposed Weaving Ligands
N
NH
NN
O
N
NH
O
N
NH
NN
O
(c) (d)
Ligand Synthesis
N
NH
O
N
NH
NN
O
NN
CH3
CH3
SeO2, py, H2ONN
O
O
OH
OH
MeOH, H2SO4NN
O
O
OMe
MeO
NN
O
O
OMe
MeO NNH2
MeOH
Evidence of the Desired Geometry
[{CoL2}CoCl4{CoL2}]
AcknowledgmentsOxidation Prof. Daryle BuschCatalysis Prof. Steve Archibald
Prof. Alan van AsseltWes Hoffert Trenton Parsell
Procter & GambleMcPherson College Stine Research Fund
MRI Contrast: Prof. Tom MeadeJonas LichtyShawn AllenAdedamola Grillo
National Institutes of HealthMcPherson College Stine Research Fund
Anti-HIV: Prof. Steve ArchibaldRobert UllomJoe BlasTaulyn Snell
McPherson College Stine Research Fund
Divergent Tim HubinMolecularTurn
Molecular David CockrielWeaving Robert UllomSociety of Self Fellows, Univ. of KansasACS Petroleum Research Fund