Chisholm Group Literature Presentation The Chemistry of Ken Raymond’s Group March 6, 2006

Chisholm Group Literature Presentation

The Chemistry of Ken Raymond’s Group

March 6, 2006

Biography

• Born 1942

• B.A. Reed College (1964)

• Ph.D. Northwestern University (1968) under Fred Basolo

• Sloan Fellow (1971)

• Visiting Professor, Stanford University (1973)

• Visiting Professor, Australian National University (1974)

• Miller Professor, Berkeley (1977)

• Visiting Professor, University Louis Pasteur, Strasbourg (1980);

• Chemistry Department Chairman (1993-1996)

• Plus Many Other Awards (Too many to list)

A Man of Many Interests: Ken Raymond

• Coordination Chemistry of Biological Iron Transport Agents

• Supramolecular Coordination Chemistry

• Lanthanide Bioinorganic Chemistry

• Actinide Coordination Chemistry

Coordination Chemistry of Biological Iron Transport Agents

• Iron is one of the most difficult nutrients to obtain for bacteria and fungi growth.

• The hydrolysis of Fe(III) limits the concentration at neutral pH to about

10-18M

• Hence, microbes produce/secrete low-molecular weight chelating agents (siderophores)

• One of the most powerful chelating siderophore is Entrobactin, and it is one of the best characterized siderophores with respect to the mechanism and genetics of its cellular transport and production.

• Entrobactin forms a remarkably stable complex with iron and is the primary siderophore of enteric bacteria.

• Entrobactin is produced from gram negative bacteria.


• Interested in Gram positive and negative transport.

• Corynebactin is an analog of entrobactin and is produced by the less studied gram-positive bacteria.


• Differences in Entrobactin and Corynebactin

– corynebactin arms contain a glycine spacer between the catecholamide and the trilactone backbone

– the trilactone backbone ring is methylated

– ferric corynebactin assumes the Λ conformation over the Δ conformation (different chirality at the iron center)



• “Modification of the seemingly perfect enterobactin structure invites many questions regarding the effect of the alterations on the uptake and stability of ferric corynebactin as compared to ferric enterobactin”


• Current work focuses on investigating the effects of these differences on gram-negative and positive transport. Several analogs of corynebactin have been synthesized to probe the effect of the spacer on iron complex stability

• Addition of an α-amino acid spacer between the backbone and the catecholamide appears to increase the stability of the iron complex

• Molecular modeling revealed a different conformation of the trithreonine backbone, allowing for formation of hydrogen bonds to neighboring amide hydrogens

• This conformation was not energetically favorable for the shorter-armed enterobactin.


• Human Protein-Bacterial Siderophore interaction. (new project?)

• The binding of enterobactin by siderocalin is evidence that the human immune system may produce proteins to bind siderophores as an immunoresponse

• Which brings us to why this study of siderophores is important.– Treatment of Iron Poisoning – Chronic Iron overload due to certain anemias– Treating of Bacterial Infections

Supramolecular Chemistry

• Spontaneous Assembly of non-covalently linked molecular clusters of unique shape and composition.

– Requires a driving force

– Requires a dynamic system

– This allows for all possible molecular structures to be explored to generate the formation of the thermodynamically favored product.

• Apoferritin is a natural example


•Lock and Key type interaction 90o and 60o apart

•Metal Ligand interactions are highly directional and can be used in place of the many weak interactions as in proteins to direct assembly.


• In principle formation of clusters of any symmetry should be possible– Need to consider the elements of a particular point group, helps in

ligand choice

• Design Considerations– Multibranched chelating ligands for increased preorganization and

stronger binding– Orientation must be rigidly fixed so unwanted stoichiometries or

geometries are avoided– Metals should be labile to fix kinetic errors to allow the formation of

thermodynamic products

• Raymond Group Ligand Choices– Catecholamide and hydroxamate ligands– High stability and lability of these chelates with +3 metal ions in

octahedral coordination– Molecular Mechanics


• Definitions: Coordination Vector

The Vector that represents the interaction between a ligand and a metal


• Definitions: Chelate Plane

The plane orthogonal to the major symmetry axis of a metal complex


• Definitions: The Approach Angle

A twist angle is a common measurement, The Approach angle has the advantage that it provides a measure that can be compared to angles generated by a high symmetry cluster

A twist angle of 60o corresponds to an approach angle of 35.3o


• Triple Helicates– Metal Sites linked by three identical C2 symmetric ligand strands– Both Metal Atoms have the same chirality– Idealized D3 symmetry

• Rational Design– C2 and C3 axes must be encoded into the ligand and metal

components– Metal Ion with psuedo-octahedral coordination and a C2-

symmetric bis(bidentate)ligand can generate the symmetry axes– Axes must be oriented 90O apart– Two chelate planes must be parallel due to metals sharing the

same C3 axis– Rigid Linkers (Direct) vs. Flexible linkers (May allow)


•Modeled by molecular mechanics

•Stoichiometry confirmed by fast atom bombardment and electrospray mass spec



• M4L6 Clusters– 4 metal atoms act as verticies of tetrahedron– Ligands act as edges of tetrahedron– Depending on the chirality at the metal center, cluster

can have C3, S4, or T idealized symmetry

• First Design Strategy– Ideally planar, C2 symmetric, bis(bidentate),Rigid

Backbone ligand

– Orientation of C2Axis, Chelate vectors at 70.6o


For this ligand a 60o angle is formed, so slight out of plane bending occurs


Crystal Structure of (Ga3+)496 shown down the S4 axis with four DMF molecules pointing into the cluster cavity.


• Second Design Strategy of M4L6

– 2 fold axis of the tetrahedron is designed to be perpendicular to the ligand plane.

– Ideally planar ligand should have antiparallel coordinate vectors



If the six ligands act as the six 2 fold symmetric faces of the polyhedron, then the angle between the chelate planes is no longer important

But the angle between the extended 2-fold plane and the C3 axis is important as this corresponds to the approach angle

Corresponds to 60o twist


Ligand 10 contains and encapsulated alkylammonium guest and the tetrahedral cluster of 11 could not be obtained with out the alkylammonium guest.

Greater Length and flexibility of anthracene ligand allow for the formation of the M2L3 structure, but just barely.

• M4L4 Complexes– Metal Ions occupy the 4 verticies

– Ligands occupy the 4 faces

– Both Ligand and metal must have 3 fold symmetry

– Octahedral geometry accomplishes this

– Again, Ligand must be rigid so the possibility of coordinating only 1 metal ion is eliminated

– If the ligand is ideally planar, then the approach angle should be about 23o which corresponds to a twist angle of 40o



The approach angle is 19.4o for this ligand, very close to the optimal 23o for complexes Ti(IV), Ga(III), and Fe(III)

Seems optimized for metal ions with significant distortions toward trigonal prismatic geometry

• The Al(III), Fe(III), Ga(III), Ti(IV), and Sn(IV) complexes were prepared

• Clusters are a racemic mixture of homochiral tetrahedra

• No Evidence of that the small cavity of the tetrahedra contains a guest



• Mixed Metal Clusters

– They do not use symmetric ligands to generate the symmetry elements

– Use different metals to generate the two symmetry elements

– Clusters are of the type M2M’3L6

– Symmetry elements to consider, 3-fold interaction site and an orthogonal 2-fold interaction site



• Catechol ligands are relatively har donors and generate a C3 axis when forming a tris-chelate with hard trivalent or tetravalent metal– Al(III), Ga(III), Fe(III), Sn(IV), Ti(IV)

• Phosphine ligands are soft ligands and can generate a 2-fold axis or mirror plane when coordinated to a square planar metal– Pd(II), Pt(II)

• A ligand with these properties can fulfill the two orthogonal symmetry requirements and can arrange into a M2M3’L6 cluster

Lanthanide Bioinorganic Chemistry

• MRI contrast Agents– Allow for determination of the 3 dimensional distribution of water

in vivo.

– Catalytically decrease the relaxation time of protons of water coordinated to a paramagnetic metal center

– Gd(III), with 7 unpaired electrons and a long electronic relaxation time, is ideally suited for such agents

– Current Gd(III)-based commercial agents have very poor contrast enhancement capabilities due to their low relaxivity

Lanthanide Bioinorganic Chemistry

• Current agents are therefore limited to targeting sites where they can be expected to accumulate in high concentrations – Blood– Kidneys

• The current challenge is to design contrast agents with higher relaxivities that will selectively localize in specific tissues or organs.

• hydroxypyridinone and mixed hydroxypyridinone-terephthalamide

based complexes – higher relaxativities– Relaxativity is due to an increase in the number of coordinated water

molecules and near-optimal water exchange rates – The high stability of the complex, and the high selectivity of the ligand

for Gd(III) over physiologically available metals such as Zn(II) and Ca(II) predicts low toxicity for these complexes

Actinide Coordination Chemistry

• Uses of Actinides– power production– ballast in ships and airplanes– ceramics– radiation shielding– heat and fuel sources in space exploration

• Causes more and more health and environmental concerns

• Similarities in Fe(III) and Pu(IV) chemistry– have similar charge to ionic size ratios – hydrolysis properties – Goes back to Siderophore research


• Project Started with Fe(III) and Pu(IV)

• Moved on to some other Actinides to help develop that chemistry (ie. Th, U, and Am)


References

• Acc. Chem. Res. 1999, 32, 975-982• Angew. Chem. Int. Ed. 2004, 43, 963• Angew. Chem. Int. Ed. 2006, 45, 83-86 • Biol. Chem. 2001, 276(10), 7209-7217• Inorg. Chem. 1991, 30, 906-911• Inorg. Chem. 1996, 35, 4128-4136• Inorg. Chem. 1999, 38, 308-315• J. Am. Chem. Soc. 2002, 124(11), 2436• J. Am. Chem. Soc. 1997, 119, 10093-10103• J. Biol. Inorg. Chem. 2000, Vol. 5, 57-66

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Chisholm Group Literature Presentation The Chemistry of Ken Raymond’s Group March 6, 2006