Topics in Molecular Topology
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Topics in Molecular Topology
Tim Hubin
Department of Chemistry and Physics
Southwestern Oklahoma State University
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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
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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
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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
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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
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BindingAffinity
Size
Geometry
Electronics
Complementarity and Binding Affinity
Complementarity
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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
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Constraint and Binding Affinity
BindingAffinity
Complementarity Constraint
Size Geometry
Electronics
Topology
Rigidity
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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
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Metal Complexes
Co(Me2B12N4)Cl2 [Ni(Me2B14N4)(acac)]+
Fe(Bn2B12N4)Cl2
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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
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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
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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
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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.
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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
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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
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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.
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Templates for Mechanical Bonds
O
O
OOH
O
OH
Br
N+
N+
Br
J. F. Stoddart J. P. Sauvage
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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.
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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.
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Proposed Weaving Ligands
N
NH
NN
O
N
NH
O
N
NH
NN
O
(c) (d)
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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
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Evidence of the Desired Geometry
[{CoL2}CoCl4{CoL2}]
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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