Department of Chemistry and Chemical Biologyhttp://www.rutchem.rutgers.edu/
 

Research Overview



Our main research playground is molecular container chemistry. Molecular containers are spherical, hollow hosts that have inner cavities large enough to accommodate one or multiple guest molecules of appropriate size and shape. Applications of molecular containers include molecular recognition, stabilization of reactive intermediates, catalysis, gas storage and separation, drug delivery, molecular sensing and nanodevice fabrication. We are primarily focusing on developing novel dynamic container molecules that respond to perturbations in the surrounding medium (e.g. pH changes) and are therefore useful for drug delivery and on the application of molecular containers as nanoreactors and catalysts. In collaborations with groups in the materials and biochemistry divisions, we are using our nanocapsules in biomedical applications, and for gas storage and separation.




Dynamic Covalent Nanocapsules


The synthesis of well-defined nanometer-size molecular capsules is a great challenge. Most approaches are based on hydrogen bond directed self-assembly or metal-ligand coordination bond formation to assemble multiple smaller building blocks into a nanocapsule However, these capsules either lack stability in aqueous medium or, if toxic metals are used, are not suitable for biomedical or biochemical applications. We have developed a rational design concept for the multi-component assembly of polycavitand nanocapsules using dynamic covalent chemistry. In this approach, components are linked together through the formation of imine or acylhydrazone bonds. The use of Schiff base chemistry is highly advantageous for several reasons: 1) Imines and acylhydrazones have well defined conformations in solution and provide a nearly linear link between two capsule building blocks. 2) Formation of both bonds is reversible. Reversibility means error correction and proof reading during the assembly process, which provides the desired nanocapsules in high yield ... often quantitative. 3) The dynamic features open up new mechanistic possibilities for guest encapsulation and release. 4) The ability to control the Schiff base equilibrium in various ways allows easy manipulation of the thermodynamic stability of the nanocapsule. 5) The imine or acylhydrazone bonds can be easily reduced, which removes the dynamic features and permanently fixes the nanocapsule.





References:

Polyimine Container Molecules and Nanocapsules. Nicholas M. Rue, Junling Sun and Ralf Warmuth, Isr. J. Chem., 2011, 51, 743-768. (Review)


One-Pot 18 Component Synthesis of an Octahedral Nanocontainer Molecule. Xuejun Liu, Yong Liu, Gina Li, Ralf Warmuth, Angew. Chem. Int. Ed. Engl., 2006, 45, 901-904.


Solvent Effects in Thermodynamically Controlled Multi-Component Nanocapsule Syntheses. Xuejun Liu and Ralf Warmuth, J. Am. Chem. Soc. 2006, 128, 14120 – 14127.



Three modular assembly strategies are currently applied in our group for the assembly of nanocapsules. In these strategies, the outcome of the nanocapsule assembly is programmed into the geometry of the building blocks.



  1. A) [6+8]-Assembly of Rhombicuboctahedral Nanocapsules


In the first strategy, six tetraformyl cavitands are reacted with eight planar, trigonal triamines or trihydrazides to yield a rhombicuboctahedral [6+8]-assembly, in which the triamines/trihydrazides occupy the triangular faces and the cavitands six of the 18 square faces of a rhombicuboctahedron. Components are held together by 24 newly formed imine of hydrazone bonds:





The first successful [6+8]-assembly was accomplished by Dr. Yong Liu. Since then, it has become our most powerful design strategy and allows for easy variation of the size of the [6+8]-assembly by using extended cavitands and/or triamine building blocks.

For example, Dr. Zhihua Lin recently assembled the nanocapsule (shown on the left) in nearly quantitative yield by reacting six extended cavitands with eight aryltrihydrazides. This capsule measures approximately 5 nanometers from top to bottom and includes a cavity with a volume of roughly 18,000 Å3, which is large enough to accommodate smaller proteins or other biomacro-molecules. Currently, Junling Sun assembles water-soluble derivatives of this capsule and explores their encapsulation properties.



Multi-component Dynamic Covalent Assembly of a Rhombicuboctahedral Nanocapsule. Yong Liu, Xuejun Liu and Ralf Warmuth, Chemistry. A European Journal 2007, 13, 8953 – 8959.


Multi-component Assembly of Cavitand-based Polyacylhydrazone Nanocapsules. Zhihua Lin, Thomas J. Emge and Ralf Warmuth, Chemistry. Eur. J., 2011, 17, 9395-9405.



  1. B)[4+8]-Assembly of Tetrahedral Nanocapsules


In our second methodology, four cavitands are linked together with eight rigid, linear diamines or bishydrazides to yield a tetrahedral [4+8]-nanocapsule, in which each cavitand is doubly linked to another cavitand and singly linked to the remaining two cavitands. This approach was developed by Dr. Xuejun Liu and is very versatile with respect to the nature of the diamino component and provides the nanocapsule in the least amount of time. For example, the [4+8]-assembly process shown below completes in less than one hour. However, we recently discovered that slight modifications of the cavitand building block yield quantitatively larger assemblies. (see section D below).




Multi-Component Synthesis of Tetracavitand Nanocapsules. Xuejun Liu, Yong Liu, and Ralf Warmuth, Supramolecular Chemistry 2008, 20, 41 - 50.




  1. C)[8+12]-Assembly of Chiral Nanocubes


In order to assemble a cube, one needs eight tritopic 90o building blocks, which occupy the eight vertices and are connected with twelve linear ditopic building blocks along the edges of the cube. Triformyltribenzylenes (CTB) are suitable tritopic units and yield quantitatively nanocubes, if reacted with a linear diamine. This [6+8]-assembly was developed by Di Xu, who also devised a dynamic approach for the kinetic resolution of the CTB, which allowed the assembly of a homochiral nanocube:





Edge-directed dynamic covalent synthesis of a chiral nanocube. Di Xu and Ralf Warmuth, J. Am. Chem. Soc., 2008, 130, 7520-7521.




  1. D)[6+12]-Assembly of a Molecular Octahedron


Recently, we extended the edge-directed assembly approach to the synthesis of nanometer-sized molecular octahedrons. In earlier work, we had discovered, that the TFA-catalyzed condensation of six cavitands Ca with twelve ethylene-1,2-diamine yields molecular octahedron Oa in 82% yield, together with small amounts of tetra-cavitand and penta-cavitand capsules. One possible reason for the sub-quantitative yield of Oa may be the geometry of cavitand Ca, which has a bite angle of 65o. To be an ideal vertex synthon for the assembly of an octahedron, the bite angle of the cavitand should be 90o. It is 85.4o in the slightly flattened cavitand Cb. Using this optimized vertex synthon, Junling Sun was able to assemble octahedrons Ob and Ob in quantitative yield, by reacting six cavitands with twelve equivalents of 1,4-phenylenediamine or benzidine, respectively. Octahedrons Ob and Ob have solvodynamic diameters of d = 3.8 and 4.7 nm, respectively.





Rational design of a nanometer-sized covalent octahedron. Junling Sun and Ralf Warmuth, Chem.

Commun., 2011, 47, 9351-9353.




pH Responsive Dynamic Cyptophanes


Related to the above described dynamic nanocapsules is the recent discovery of a dynamic cryptophane, which assembles spontaneously from two cyclotribenzylenes and three diamines upon addition of an appropriate templating guest. This dynamic system, which was developed by Dr. Cécile Givelet, displays very interesting features. It responds to the pH of the medium and the addition or removal of the guest template. Currently, Nicholas Rue investigates the molecular recognition properties of dynamic cryptophanes and related dynamic hemicarcerands and their use as nanoreactors or catalysts.





Templated dynamic cryptophane formation in water. Cécile Givelet, Junling Sun, Di Xu, Thomas J. Emge, Ashwini Dhokte and Ralf Warmuth. Chem. Commun., 2011, 47, 4511 - 4513.




Encapsulated Reactive Intermediates


Hemicarcerands are preeminently suited as molecular reaction flasks for the inner phase stabilization of reactive intermediates. Hemicarcerands are spherical, hollow hosts that are constructed from two cavitands linked together with four connectors. They have inner cavities (the inner phase) that are large enough to accommodate a single organic guest molecule. For example, the hemicarcerand shown on the right, forms stable complexes (hemicarceplexes) with guests ranging in size from benzene to naphthalene. In a hemicarceplex, the guest is almost fully surrounded by the host and shielded from interaction with bulk phase components. Hemicarceplexes are very stable. Dissociation requires high temperature due to the large activation energy that has to be overcome when the guest passes through one of the size restricted openings in the host shell.


The possibility to photolyze incarcerated guest molecules opens up the opportunity to generate and protect highly strained and reactive molecules inside carcerands. A suitable, photochemical precursor molecule is first incarcerated. Photolysis of the guest yields the reactive intermediate in the inner phase. Once generated, the surrounding host prevents destructive reactions, such as dimerization or trapping with bulk phase reactants that are too large to pass through an opening in the host shell. This makes possible NMR spectroscopic characterization of otherwise fleeting species, which complements other spectroscopic techniques, such as matrix isolation spectroscopy, time-resolved spectroscopy or flow techniques and provides new insight into the electronic and structural properties and reactivity of important organic intermediates.


We have applied the concept of stabilization by incarceration in our investigation of arynes, carbenes, nitrenes and of highly strained cyclic allenes, ketenimines and anti-Bredt olefins.



General References:

Reactions Inside Carcerands. Ralf Warmuth, in Molecular Encapsulation: Reactions in Constrained Systems, Udo H. Brinker, Jean-Luc Mieusset (Eds.), John Wiley, 2010, Chapter 9, 227-268.


Inner Phase Stabilization of Reactive Intermediates. Ralf Warmuth, Eur. J. Org. Chem., 2001, Vol. 2001, 423-437.


The Inner Phase of Molecular Container Compounds as a Novel Reaction Environment. Ralf Warmuth, J. Inclusion Phenomena and Molecular Recognition in Chemistry, 2000, 37, 1-38.




Helix Nucleation Sites


In addition to our work on container molecules, we are interested in developing new ways to conformationally constrained short peptides, which is an important area of medicinal chemistry. Benefits are multiple. Most peptides adapt a large ensemble of conformations in solution. If a peptide binds to a receptor in a specific conformation, locking it in this conformation, will result in a substantially increased potency of the peptide. Constrained peptides also play an important role in quantifying propensities of amino acids for secondary structures, which is a prerequisite for correctly predicting structures of de novo peptides and proteins. Recently, we have designed and a alpha-helix nucleation site shown on the right, which is able to induce and stabilize a helical conformation in short peptides that would be unstructured otherwise.



Asymmetric Synthesis of two new Conformationally Constrained Lysine Derivatives. Ralf Warmuth, Tamara E. Munsch, Robert A. Stalker, Jacquelyn D. Tran, Xiaoping Nie, Alicia Beatty, and Christer Aakeroy, Tetrahedron, 2002, 58, 4837-4849.