Transcript Research Interests - Southwestern Oklahoma State University

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)
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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
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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