Raymond Group Research

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Supramolecular Coordination Chemistry
Introduction

The Raymond group has developed a predictive design strategy resulting in the synthesis of various high-symmetry coordination clusters, including M2L3 helicates and mesocates; M4L6 and M4L4 tetrahedra; M6L6 and M8L8 cylinders; and M8L6 octahedra. These examples all focus on the coordination of three bidentate chelators to a tri- or tetravalent metal ion in a pseudo-octahedral fashion at the apices of the clusters to generate local three-fold symmetry at these metal centers. These chelators are contained in rigid, symmetric multi(bidentate)-ligands which supply the other symmetry elements of the cluster (2-fold, 3-fold, or mirror plane). By simultaneously fulfilling the symmetry requirements of both the ligand and metal centers, discrete high-symmetry clusters are generated under thermodynamic control. We are exploring the self-assembly of new clusters, thermodynamics and kinetics of cluster formation and host-guest interactions, electrochemistry, luminescence, ligand exchange, and chiral resolution and isomerization in the context of these supramolecular clusters.


Cluster Design and Synthesis

Our design strategy has already allowed us to generate many different cluster architectures, as mentioned above. Self-assembly of helicate complexes of the formula [M2L3]6- and tetrahedral complexes with the formula [M4L6]12- can be achieved via the self-assembly of an octahedrally coordinating, trivalent metal ion (e.g., Fe3+ or Ga3+) with an appropriate bis-bidentate ligand, L. The use of diamagnetic Ga3+ in the synthesis of these clusters has enabled study of these novel molecules by NMR spectroscopy, as these highly symmetric molecules have a distinctly simple spectrum, shifted from that of the free ligand.

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Three-fold symmetric tris-bidentate ligands have been used to synthesize clusters with triangular faces, such as M4L4 tetrahedra, M6L6 and M8L8 rings, and M6L8 octahedra. Again a labile tri- or tetra-valent metal ions is used as the vertex of the given topology, but the ligand comprises a face of the cluster, rather than an edge as in the earlier example.

A continuing pursuit in our laboratories focuses on the synthesis of new cluster topologies, as well as generating larger versions of the clusters we already have in hand. For example, the use of a five-fold symmetric ligand may allow for formation of a cluster with icosahedral symmetry, whereas using "expanded" versions of our new ligands, we hope to synthesize clusters with larger cavities.

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Biros, S. M.; Yeh, R. M.; Raymond, K. N. "Design and Formation of a Large, Supramolecular Cluster Using 1,1'-Binaphthyl Ligands," Angew. Chem. Int. Ed. 2008, 47, 6062-6064.

Yeh, R. M.; Xu, J.; Seeber, G.; Raymond, K. N. "Large M4L4 (M = Al(III), Ga(III), In(III), Ti(IV)) Tetrahedral Coordination Cages: an Extension of Symmetry-Based Design." Inorg. Chem. 2005, 44, 6228-6239.

Caulder, D. L.; Brückner, C.; Powers, R. E.; König, S.; Parac, T. N.; Leary, J. A.; Raymond, K. N. "Design, Formation and Properties of Tetrahedral M4L4 and M4L6 Supramolecular Clusters." J. Am. Chem. Soc. 2001, 123, 8923-8938.

Terpin, A. J.; Ziegler, M.; Johnson, D. W.; Raymond, K. N. "Resolution and Kinetic Stability of a Chiral Supramolecular Assembly Made of Labile Components." Angew. Chem. Int. Ed. 2001, 40, 157-160.

Xu, J.; Raymond, K. N. "Lord of the Rings: An Octameric Lanthanum Pyrazolonate Cluster." Angew. Chem. Int. Ed. 2000, 39, 2745-2747.

Parac, T. N.; Scherer, M.; Raymond, K. N. "Host within a Host: Encapsulation of Alkali Ion-Crown Ether Complexes into a [Ga4L6]12- Supramolecular Cluster." Angew. Chem. Int. Ed. 2000, 39, 1239-1242.

Johnson, D. W.; Xu, J.; Saalfrank, R. W.; Raymond, K. N. "Self Assembly of a Three Dimensional Ga6L6 Metal Ligand 'Cylinder.'" Angew. Chem. Int. Ed. Engl. 1999, 38, 2882-2885.

Sun, X.; Johnson, D. W.; Caulder, D. L.; Powers, R. E.; Raymond, K. N.; Wong, E. H. "Exploiting Incommensurate Symmetry Numbers: Rational Design and Assembly of M2M'3, L6 Supramolecular Clusters with C3h Symmetry." Angew. Chem. Int. Ed. Engl. 1999, 38, 1303-1307.

Brückner, C.; Powers, R. E.; Raymond, K. N. "Symmetry-Driven Rational Design of a Tetrahedral Supramolecular Ti4L4 Cluster." Angew. Chem. Int. Ed. 1998, 37, 1837-1839.


Host-Guest Chemistry

The host-guest chemistry of the chiral tetrahedral [Ga4L6]12- assembly, where L = 1,5-bis(2,3-dihydroxybenzamido)naphthalene, has been investigated extensively.

Leung, D. H.; Bergman, R. G.; Raymond, K. N. "Enthalpy-Entropy Compensation Reveals Solvent Reorganization as a Driving Force for Supramolecular Encapsulation in Water," J. Am. Chem Soc. 2008, 130. 2798-2805.

Pluth, M. D. and Raymond, K. N. "Reversible Guest Exchange Mechanisms in Supramolecular Host-Guest Assemblies." Chem. Soc. Rev. 2007, 36, 161-171. (Selected by journal for enriched HTML.)

Davis, A. V.; Fiedler, D.; Seeber, G.; Zahl, A.; van Eldik, R.; Raymond, K. N. "Guest Exchange Dynamics in an M4L6 Tetrahedral Host." J. Am. Chem. Soc. 2006, 128, 1324-1333.

Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R.G.; Raymond, K. N. "Molecular Recognition of Iminium Ions in Water." J. Am. Chem. Soc. 2006, 128, 14464-14465.

Davis, A. V. and Raymond, K. N. "The Big Squeeze: Guest Exchange in an M4L6 Supramolecular Host." J. Am. Chem. Soc. 2005, 127, 7912-7919.


A Capsule with a Dangling Guest

Normally, a molecule must be either inside or outside the cavity at any given time. But when a molecule with both cationic guest and repulsive negative terminus components is used, one end of the molecule is encapsulated by the host, while the other end remains outside the capsule. Since doing chemistry inside the chiral, nanoscale environment of the cluster requires reactants to enter and product to leave, it is important to demonstrate the feasibility and mechanism of this process. Thus, guests were designed, which would be encapsulated but would dangle one end out of the cavity. A hydrocarbon chain served as the linker, with a positively-charged group -- known to act as a guest by itself -- at one end, and a negatively-charged group at the other. When dissolved in water with the negatively-charged host cluster, the positive end winds up inside the capsule, but the negative end of the same molecule remains outside. The slender hydrocarbon chain pokes through one of the expandable gaps, allowing the negative tail to dangle in the water surrounding the capsule. The NMR signals of the exterior and interior methylene protons clearly show these relative positions, and mass spectra show that the guest flies with the host cluster. While simple, this approach is extremely effective -- with the right chain length, binding constants upwards of 104 have been achieved!

Tiedemann, B. E. F. and Raymond, K. N. "Second-Order Jahn-Teller Effect in a Host-Guest Complex." Angew. Chem. Int. Ed. 2007, 46, 4976-4978.

Tiedemann, B. E. F. and Raymond, K. N. "Dangling Arms: A Tetrahedral Supramolecular Host with Partially Encapsulated Guests." Angew. Chem. Int. Ed. 2006, 45, 83-86.


Supramolecular Catalysis

In collaboration with the Bergman Group

Molecules encapsulated within a supramolecular host are subject to a unique chemical environment in which reactions take place with enhanced rates or selectivity. In a joint study with the Robert G. Bergman Research Group, we are investigating organic and organometallic reactions mediated or catalyzed by M4L6 tetrahedral clusters.

Pluth, M. D.; Bergman, R. G.; Raymond, K. N. "Selective Stoichiometric and Catalytic Reactivity in the Confines of a Chiral Supramolecular Assembly," chapter in Supramolecular Catalysis; Ed. Piet W. N. M. van Leeuwen, Wiley-VCH, 2008; pp. 165-191.

Fiedler, D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. "Selective Molecular Recognition, C-H Bond Activation, and Catalysis in Nanoscale Reaction Vessels," Acc. Chem. Res. 2005, 38, 351-360.



Organometallic Reactivity within a Supramolecular Host

Since many of these supramolecular assemblies provide large cavities that can encapsulate monocationic guests, we have turned towards the encapsulation of chemically reactive monocationic organometallic species. The cavity of the nanovessel provides a distinct, well-ordered and chiral environment that may affect the reactivity of the encapsulated metal complex.

The naphthalene-based tetrahedral [Ga4L6]12- host has been shown to encapsulate a variety of organometallic half-sandwich iridium complexes in aqueous solution. This encapsulation has been shown to be highly dependent on both the size and shape of the iridium guest. Modest to good diastereoselectivities of encapsulation can be observed. In addition, some of these iridium host-guest assemblies react with organic substrates such as aldehydes and ethers via C-H bond activation, which occurs within the host interior. The well-defined shape of the host cavity serves to direct the reactivity of the guest with high size and shape selectivity as well as modest diastereoselectivity that is not seen with the unencapsulated species.

This supramolecular assembly has also been used to mediate a catalytic organometallic reaction: an encapsulated bisphosphine-Rh(I) complex, like the corresponding unencapsulated complex, catalyzes the isomerization of allylic alcohols and ethers to aldehydes and enol ethers, respectively. The reaction takes place within the confines of the host cavity, and exhibits strict size and shape selectivity.



In collaboration with the Toste group, we have also begun exploring the reactivity of Au (I) catalysts.  Upon encapsulation in [Ga4L6]12-, an 8-fold rate acceleration was observed for the catalytic hydroalkoxylation of allenes.  This example is the first in which the encapsulation of a gold catalyst has led to an enhancement in both rate and TON.
gold

Wang, J. Z.; Brown, C. J.; Bergman, R. G.; Raymond, K. N; F. Dean Toste. "Hydroalkoxylation Catalyzed by a Gold (I) Complex Encapsulated in a Supramolecular Host." J. Am. Chem. Soc. 2011, 133, 7358-7360.

Leung, D. H.; Bergman, R. G.; Raymond, K. N. "Highly Selective Supramolecular Catalyzed Allylic Alcohol Isomerization." J. Am. Chem. Soc. 2007, 129, 2746-2747.

Leung, D. H.; Bergman, R. G.; Raymond, K. N. "Scope and Mechanism of the C-H Bond Activation Reactivity within a Supramolecular Host by an Iridium Guest: A Stepwise Ion Pair Guest Dissociation Mechanism." J. Am. Chem. Soc. 2006 128, 9781-9797.

Fiedler, D.; Bergman, R. G.; Raymond, K. N. "Stabilization of Reactive Organometallic Intermediates inside a Self-Assembled Nanoscale Host." Angew. Chem. Int. Ed., 2006, 45, 745-748.

Leung, D. H.; Fiedler, D.; Bergman, R. G.; Raymond, K. N. "Selective C-H Bond Activation by a Supramolecular Host-Guest Assembly." Angew. Chem. Int. Ed. 2004, 43, 963-966.



Supramolecular Acceleration of Organic Reactions
Sigmatropic Rearrangements

The supramolecular metal-ligand assembly can also be employed as a catalytic host for the unimolecular carbon-carbon bond-forming rearrangement of enammonium cations. The restricted reaction space of the supramolecular structure forces the substrates to adopt a reactive conformation upon binding to the interior. With no transition state-stabilizing functional groups within the cavity, the assembly achieves up to 1000-fold rate acceleration of the rearrangement. Release and hydrolysis of the product allow for catalytic turnover.  Carrying out the aza-Cope reaction within enantiopure homochiral [Ga4L6]12- results in enantioselectivities of 4-64% at 50 °C, up to 78% ee at 5 °C. 

Brown, C. J.; Bergman, R. G.; Raymond, K. N. "Enantioselective Catalysis of the Aza-Cope Rearrangement by a chiral Supramolecular Assembly," J. Am. Chem. Soc. 2009, 131, 17530-17531.

Hastings, C. J.; Fiedler, D.; Bergman, R. G.; Raymond, K. N. "Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled 'Nanozyme'," J. Am. Chem. Soc. 2008, 130, 10977-10983.

Fiedler, D.; van Halbeek, H.; Bergman, R. G.; Raymond, K. N. "Supramolecular Catalysis of Unimolecular Rearrangements: Substrate Scope and Mechanistic Insights." J. Am. Chem. Soc. 2006 128, 10240-10252. (Subject of an Editor's Choice commentary in Science 2006, 313, 735.)

Fiedler, D.; Bergman, R. G.; Raymond, K. N. "Supramolecular Catalysis of a Unimolecular Transformation: Aza-Cope Rearrangement within a Self-Assembled Host." Angew. Chem. Int. Ed. 2004, 43, 6748-6751. (Cover article. Subject of an Angewandte Highlight: A. Lützen, Angew. Chem. Int. Ed. 2005, 44, 1000- 1002.)



Proton-catalyzed Reactions

The [M4L6]12- assembly has a preference for cationic guests, and preferentially encapsulated protonated amines and phosphines with respect to the neutral, unprotonated form. This thermodynamic preference leads to the encanced basicity of amines encapsulated inside of the assembly. We have observed amines which are up to 4 pKa units more basic in the assembly than in free solution, which approaches the magnitude of pKa shifts found in nature (e.g. enzymes).

We have used these shifts in the basicity of encapsulated guests to affect the reactivity of acid-catalyzed reactions. For example, the acid-catalyzed hydrolysis of orthoformates or acetals in basic solution can be carrier out inside of the assembly with rate accelerations of up to 103 when compared to the background reaction. Furthermore, the catalyzed reaction obeys Michaelis-Menten kinetics, exhibits competitive inhibition, and the substrate scope displays size selectivity consistent with the constrained binding environment of the molecular host.

Pluth, M. D.; Bergman, R. G.; Raymond, K. N. "Encapsulation of Protonated Diamines in a Water-Soluble, Chiral, Supramolecular Assembly Allows for Measurement of Hydrogen-Bond Breaking Followed by Nitrogen Inversion/Rotation," J. Am Chem. Soc. 2008, 130, 6362-6366.

Pluth, M. D.; Bergman, R. G.; Raymond, K. N. "Catalytic Deprotection of Acetals in Strongly Basic Solution Using a Self-Assembled 'Nanozyme'," Angew. Chem. Int. Ed. 2007, 46, 8587-8589.

Pluth, M. D.; Bergman, R. G.; Raymond, K. N. "Making Amines Strong Bases: Thermodynamic Stabilization of Protonated Guests in a Highly-Charged Supramolecular Host." J. Am. Chem. Soc. 2007, 129, 11459-11467.

Pluth, M. D.; Bergman, R. G.; Raymond, K. N. "Acid Catalysis in Basic Solution: A Supramolecular Host Promotes Orthoformate Hydrolysis." Science 2007, 316(5821), 85-88. (Subject of C&EN concentrate 2007, 85(15), 36.)


The Nazarov Cyclization

By combining proton-catalyzed reactivity with the sterically constrained environment of the [Ga4L6]12- assembly, we have measured enormous rate accelerations (up to 2,100,000-fold) for the Nazarov cyclization to prepare Cp*.  These rate accelerations are unprecedented in the field of supramolecular catalysis.

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Hastings, C. J.; Bergman, R. G.; Raymond, K. N. "Enzymelike Catalysis of the Nazarov Cyclization by Supramolecular Encapsulation" J. Am. Chem. Soc. 2010, 132, 6938-6940.

Solution Dynamics and Cluster Resolution

As the design and synthesis of supramolecular assemblies becomes more accessible, we are interested in characterizing their solution behavior. Understanding of the dynamic behavior of these species may be particularly important as we endeavor to develop the chemistry of nanoscale reaction flasks.

An intriguing feature of some of our supramolecular assemblies is that they are chiral; we have reported formation of homochiral supramolecular assemblies from achiral, labile metal-ligand systems. Study of the racemization of these species advances our description of the dynamic behavior of supramolecular coordination clusters in general. Initially, racemization of a homochiral M2L36- cluster (a helicate) was investigated and characterized as proceeding by a Bailar Twist mechanism. Proton independent and proton dependent mechanisms were elucidated and reported.

Chiral resolution of a racemic (ΔΔΔΔ and ΛΛΛΛ mixture) homochiral M4L612- cluster (3) with a chiral counter ion allowed for investigation of the racemization of a larger system. We predicted that the mechanical coupling between metal centers which forces the structure to be homochiral, would also inhibit cluster racemization. A solution (at pH = 10) of the resolved ΔΔΔΔ-[Et4N ⊂ M4L6]11- was monitored by CD spectroscopy for three months, and indeed, no cluster racemization was observed. From labile metal-ligand components an inert chiral species is created!

Another dynamic behavior exhibited by certain supramolecular species is the interconversion between two discrete assembly forms. Such a process has been reported in several labile systems. The driving force is often thermodynamic stabilization of the new form through host-guest interaction. We have reported two such examples: conversion of M2L3 helicate (8) to M4L6 tetrahedron (2) and conversion of (ΔΛ) mesocate to (ΔΔ, ΛΛ) helicate (1). In both processes, guest encapsulation was determined to be the driving force. Thermodynamic parameters were reported for the mesocate-helicate system, and we have begun to investigate the helicate-tetrahedron conversion process.

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Xu, J.; Parac, T. N.; Raymond, K. N. "Meso Myths: What Drives Assembly of Helical versus Meso M2L3 Clusters?" Angew. Chem. Int. Ed. Engl. 1999, 38, 2878-2882.

Scherer, M.; Caulder, D. L.; Johnson, D. W.; Raymond, K. N. "Triple Helicate--Tetrahedral Cluster Interconversion Controlled by Host-Guest Interactions." Angew. Chem. Int. Ed. Engl. 1999, 38, 1587-1592.

Parac, T. N.; Caulder, D. L.; Raymond, K. N. "Selective Encapsulation of Aqueous Cationic Guests into a Supramolecular Tetrahedral [M4L6]12- Anionic Host." J. Am. Chem. Soc. 1998, 120, 8003-8004.

Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N. "The Self-Assembly of a Pre-designed Tetrahedral M4L6 Supramolecular Cluster." Angew. Chem. Int. Ed. 1998, 37, 1840-1843.

Caulder, D. L.; Raymond, K. N. "Supramolecular Self-Recognition and Self-Assembly in Gallium(III) Catecholamide Triple Helices." Angew. Chem. Int. Ed. 1997, 36, 1439-1442.


Collaborators

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