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