Transcript Chisholm Group Literature Presentation

Chisholm Group Literature
Presentation
The Chemistry of Ken Raymond’s
Group
March 6, 2006
Biography
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Born 1942
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B.A. Reed College (1964)
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Ph.D. Northwestern University (1968) under Fred Basolo
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Sloan Fellow (1971)
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Visiting Professor, Stanford University (1973)
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Visiting Professor, Australian National University (1974)
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Miller Professor, Berkeley (1977)
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Visiting Professor, University Louis Pasteur, Strasbourg (1980);
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Chemistry Department Chairman (1993-1996)
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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
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Iron is one of the most difficult nutrients to obtain for bacteria and fungi
growth.
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The hydrolysis of Fe(III) limits the concentration at neutral pH to about
10-18M
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Hence, microbes produce/secrete low-molecular weight chelating agents
(siderophores)
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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.
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Entrobactin forms a remarkably stable complex with iron and is the primary
siderophore of enteric bacteria.
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Entrobactin is produced from gram negative bacteria.
Coordination Chemistry of Biological Iron
Transport Agents
• Interested in Gram positive and negative transport.
• Corynebactin is an analog of entrobactin and is
produced by the less studied gram-positive bacteria.
Coordination Chemistry of Biological Iron
Transport Agents
• 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)
Coordination Chemistry of Biological Iron
Transport Agents
Coordination Chemistry of Biological Iron
Transport Agents
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“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”
Coordination Chemistry of Biological Iron
Transport Agents
• 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 shorterarmed enterobactin.
Coordination Chemistry of Biological Iron
Transport Agents
• 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
Supramolecular Chemistry
•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.
Supramolecular Chemistry
• 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
Supramolecular Chemistry
• Definitions: Coordination Vector
The Vector that represents the interaction between a ligand and a metal
Supramolecular Chemistry
• Definitions: Chelate Plane
The plane orthogonal to the
major symmetry axis of a
metal complex
Supramolecular Chemistry
• 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
Supramolecular Chemistry
• 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 C2symmetric 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)
Supramolecular Chemistry
•Modeled by molecular mechanics
•Stoichiometry confirmed by fast atom bombardment and electrospray mass spec
Supramolecular Chemistry
Supramolecular Chemistry
• 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
Supramolecular Chemistry
For this ligand a 60o angle is formed, so slight out of plane bending occurs
Supramolecular Chemistry
Crystal Structure of (Ga3+)496
shown down the S4 axis with
four DMF molecules pointing
into the cluster cavity.
Supramolecular Chemistry
• 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
Supramolecular Chemistry
Supramolecular Chemistry
Corresponds to
60o twist
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
Supramolecular Chemistry
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.
Supramolecular Chemistry
• 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
Supramolecular Chemistry
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
Supramolecular Chemistry
• 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
Supramolecular Chemistry
• 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
Supramolecular Chemistry
Supramolecular Chemistry
• 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
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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
Actinide Coordination Chemistry
• Project Started with Fe(III) and Pu(IV)
• Moved on to some other Actinides to help
develop that chemistry (ie. Th, U, and Am)
Actinide Coordination Chemistry
References
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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