The molecular matryoshka

Nature can assemble complex structures in a single step so why can't we? Well we can, if we know enough about supramolecular chemistry and bring together the right ingredients. Chemists are discovering how 'hooks, eyes, buckets and lids' can form versatile little capsules.

Like a chemical version of the famous nesting Russian dolls, molecules that contain other molecules could be used to trap other even smaller molecules inside. Such structures could be used as tiny chemical reactors, as building blocks for smart materials, and maybe one day as drug delivery agents. Best of all these molecules can put themselves together with minimal assistance from chemists.

Leeds University's Dr Michaele Hardie and Professor Colin Raston, who is now at the University of Western Australia in Perth, together with Professor Jerry Atwood and colleagues at the University of Missouri-Columbia in the USA, are working with EPSRC support: "This international collaboration is part of an ongoing research network established over a decade ago, and involves a PhD exchange program," explains Professor Raston. The team's focus has turned to supramolecular chemistry to help them design and build a range of submicroscopic capsules.

[image] Diagram showing two spheres linked by a 'Russian Doll' connection. The cuboctahedral symmetry of the sphere is indicated.

In conventional synthetic chemistry, chemists carefully choose reaction ingredients, mix them together, perhaps heat the mixture or add a catalyst. They then watch until old bonds between atoms break and new ones form turning the starting ingredients into an intermediate. They then fish out this intermediate using various separation techniques, add a second set of reactants, adjust the reaction temperature, and wait until the next intermediate forms and so on. Chemists often use this long-winded approach to make sophisticated molecules.

The anticancer drug Taxol, for instance, which contains 47 carbon atoms, 51 hydrogen atoms, 14 oxygen atoms and a nitrogen, all arranged in rings and branches of various sizes and connections, has dozens of bonds to make. The simplest synthesis takes around 20 reaction steps from initial starting materials to end product.

In stark contrast, to undertake a supramolecular chemical reaction the chemists simply throw all the starting materials in a reaction flask, adjust the temperature, add a catalyst if required and leave the brew to do its job - extracting the product in a final step. So, how does this work? How can molecules self-assemble in this way?

Nature provided chemists with the inspiration for supramolecular chemistry. Biochemical reactions rarely involve more than a handful of steps from starting material to final product. The key lies in the 'design' (by evolution) of the building blocks for these processes. With the right building blocks there is no need for the dozens of bond making and breaking steps to rearrange atoms into a new molecule. The pieces simply slot together.

Molecular 'velcro'

The formation of the double helix of DNA and the construction of a viral protein coat involve supramolecular chemistry. The common factor is that the permanent bonds within molecules that stitch atoms together don't change, it is bonds between molecules that form to hold the pieces together. Whereas bonds within molecules are like permanent stitching, supramolecular bonds are more like velcro fasteners - where complementary hooks and eyes link the units.

Another important example of supramolecular chemistry in action involves the enzymes, nature's catalysts. These complex folded molecules, sometimes containing thousands of atoms, usually have a hollow site which acts as a 'host' for smaller 'guest' molecules and can transform those guests into other molecules catalytically. Protein molecules too can have such hollows to transport smaller guest molecules within the cell, while receptors trap their guests and emit a signal to tell the cell they have done so.

With these two strands of supramolecular chemistry in mind - the self-assembly of sophisticated molecules from simpler building blocks and the host-guest principle - Hardie, Raston and their colleagues have stripped the host concept down to its bare bones to build molecules that can bind other molecules, rather like the active site in an enzyme or protein but with no biological baggage.

[image] Lid-shaped molecules known as crown ethers are brought together with bucket-like molecules called calixarenes (image: Russian Doll assembly with p-sulfonatocalix[6]arene, crown ether and terbium cations).

"Our approach allows us to assemble very complicated structures from simple molecules that are relatively easy to make," Dr Hardie explains. Other chemists had used self-assembly to build ring-shaped and bowl-like molecules for holding other small molecules. However, there is a limit to what these molecules can do and the size of the guests they can accommodate.

Raston, Hardie and their colleagues have now taken the next logical step - to create much bigger hosts by making the container molecules themselves self-assemble into large capsules. They designed and synthesised a range of bucket-like molecules (calixarenes) and added special chemical groups around the rim of each bucket to act as the velcro 'hooks' for supramolecular interactions. They then attached the complementary chemicals (the 'eyes') to a set of lid-shaped molecules known as crown ethers.

"We've nicknamed these capsules 'Russian Dolls'," says Dr Hardie, "as they have several levels of smaller molecules contained inside larger molecules. Importantly, these capsules can be further assembled into even more complicated molecules."

Buckets and lids

When the team mixed the buckets and lids, the molecular velcro fastens the lids to the buckets making an enclosed capsule shape. By adding different buckets and lids to the reaction mixture, supramolecular chemistry leads to a range of capsules of different sizes and shapes built from different combinations of buckets and lids. The team could control which combination was produced by tweaking the reaction conditions, the pH, temperature and reaction solvent. "By doing so, we could generate complicated molecules ranging from zig-zagging chains to a very large spherical assembly of twelve bucket-like molecules," adds Dr Hardie.

This latter molecular assembly has a very large internal space and, importantly, smaller pores on its surface. "The pores may allow for the transport of molecules into and out of the sphere," says Dr Hardie, "thus the sphere may be able to be a nano-reaction flask for other chemical reactions, or be a molecular-transport device."

[image] Zigzag chain of p-sulfonatocalix[6]arene, crown ether and europium cations.

Crucially, for many applications, the chemical hooks also carry a negative charge countered by the presence of a positive metal ion, which ensures that the resulting capsules dissolve in water. Water solubility will make these molecular capsules much more useful in medical applications, for instance, where organic solvents cannot be used. "As we as supramolecular chemists become better at constructing larger and more complex assemblies from simple molecules then we'll find new insights into tailoring self-assembled systems which may lead to the eventual mimicking of biological systems, as well as chemical and materials applications," says Dr Hardie.

The researchers are not finished designing and building their molecular matryoshka though: "There is much to be done in understanding the basic self-assembly processes in order to drive the potential applications," adds Professor Raston. "These include drug delivery, nano-particle technology, controlling chemical reactions (nano-flask technology) and more."