Supramolecular chemistry: Moving away from synthesis and toward design

Jean-Marie Lehn (Image: Wikipedia Commons)

The key goal of chemical science in the nineteenth and twentieth century was to understand how atoms come together to form molecules through chemical bonds. The focus was thus on understanding the covalent interactions that link atoms together, interactions that are made possible by the sharing of electrons. The theory of chemical bonding achieved its pinnacle in the development of quantum chemistry by pioneers like Linus Pauling, Robert S. Mulliken, John S. Slater, John Pople and Walter Kohn.

This understanding was critical for the one activity that makes chemistry unique, sets it apart from physics and biology as a creative science and underlies the high standard of living that the world enjoys today – synthesis. While the 19th century laid the foundations of classifying chemical compounds and making simple ones, the science of chemical synthesis was honed to the status of an art form in the twentieth century. Singular scientists like Robert Robinson, Robert B. Woodward and Elias James Corey drew on theoretical principles of chemical bonding and combined this theory with an exhaustive set of experimental data collected over two centuries to turn chemical synthesis into a precisely rational science. They demonstrated that given enough time, funds and manpower, virtually any chemical compound of arbitrary complexity can be synthesized.

However these pioneers of synthesis succeeded all too well. So complete was their understanding of the principles of organic synthesis and so spectacular and prolific were their achievements that by the time the dust settled, the general problem of complex synthesis had been solved. That is not to say that specific syntheses challenges would not tax the minds of bright young scientists. It’s just that the answer to the general question of whether a particular compound could be synthesized had been confirmed to be a resounding yes. Synthesis, while still central to chemists’ world, has turned into a tool rather than an end in itself. Today graduate students can synthesize in a week what would take years even for the world’s best chemists to make in the 1960s. Nobody seriously thinks now that synthesizing a molecule, no matter how complicated, is revolutionary rather than evolutionary science.

If synthesis is no longer chemistry’s grand challenge, what is? Part of the answer was provided this morning by Jean-Marie Lehn in Lindau . While Woodward and Corey were appearing on front pages of journals and magazines through their conspicuous covalent accomplishments, a silent and underappreciated revolution was taking place in the domain of non-covalent interactions. By the 1960s non-covalent interactions like hydrogen bonds had already been recognized to be critical for biochemistry. The pioneers of protein and nucleic acid structure like Pauling, Perutz, Watson and Crick had proven the key role that hydrogen bonds play in holding proteins and DNA together. But non-covalency had yet to be accepted along with covalent bond formation as a tool of equal synthetic capability. That changed with the work of Lehn, Donald Cram and Charles Pederson whose work led to them being awarded the 1987 Nobel Prize in chemistry. It’s interesting to note that the last Nobel Prize for traditional organic synthesis was given in 1990 to Elias James Corey. So in one sense the beginnings of non-covalent synthesis can be seen to coincide with the recognition of covalent organic synthesis as a science which had reached its pinnacle.

We are still very much at the beginnings of the revolution that Lehn, Cram, Pederson and others have engineered. Lehn called the study of the structure and synthesis of non-covalently built compounds ‘supramolecular chemistry’. Supramolecular chemistry critically hinges on the phenomenon of self-assembly or self-organization that operates in an astonishing diversity of applications, from the working of detergents to the origin of life. The great advantage of non-covalent association is that, unlike covalent bond formation, it is reversible. Life as we know it would be impossible if molecules bound to each other permanently. Complex physiological responses require both molecular association as well as dissociation. Only supramolecular chemistry can help us understand this dynamic interplay between molecules. Supramolecular chemistry also explains specificity, the preferential association of molecules that keeps biological systems from disintegrating into a cacophony of energetically costly, potentially harmful interactions. Most importantly, in its ability to bridge the behavior of molecules with that of collections of molecules, supramolecular chemistry inherently includes an understanding of the emergent phenomena that are at the heart of understanding complex systems.

We still don’t understand the principle of supramolecular, non-covalent self-assembly well enough to be able to predict how a motley group of molecules thrown together in a test-tube will come together to form complex structures. Both experimental and computational developments will undoubtedly provide insights into this predictive capability. The flip side of this ignorance is the wonderment experienced at watching very simple chemical compounds form intricate and fascinating architectures that display unprecedented specificity and affinity. Lehn cited an example of two kinds of molecules, one of which forms double helices and the other forms triple helices. Throw millions of the individual monomers together and you will get only double helix pairs and triple helix pairs and no double-triple helix hybrids. This kind of specific supramolecular self-organization has potential applications in every conceivable field. Lehn and his co-workers themselves synthesized crown ethers and cryptands which trap ions; these compounds can be used in a variety of tasks, from water purification to the removal of toxic metals in living systems. Other supramolecular complexes shown by Lehn formed grids which could serve as electronic devices, fluorescent sensors and mini-enzymes. Supramolecular chemistry is thus mainly about design rather than synthesis; the synthetic capability is built into the very structure of the molecules, and this capability is harnessed by self-assembly without extensive outside intervention.

A “foldamer” synthesized by Lehn’s group. Foldamers are molecules that are engineered to spontaneously fold into well-defined shapes that can perform certain functions (Image: Wikipedia Commons).

Finally, supramolecular organization was key to the origin of life. We now have a good understanding of how simple groupings of atoms might have come together under primordial conditions to form the basic building blocks of life like nucleic acid bases, sugars and amino acids. What we still lack is an understanding of how these building blocks talked to each other through non-covalent association and dissociation to form the intricate signaling networks that underlie life’s workings, and this is where supramolecular chemistry can provide tantalizing clues. If we can understand how this all-important transition between simple and complex matter occurred, it will help us to understand what is perhaps the most important transition in the history of the universe: the transformation of non-living matter into self-aware, conscious, sentient, living creatures.

Ashutosh Jogalekar

About Ashutosh Jogalekar

Ashutosh Jogalekar is a scientist and science writer based in Boston, USA. He has been blogging at the “Curious Wavefunction” blog for more than ten years, and in this capacity has written for several organizations including Scientific American and the Lindau Nobel Laureate Meetings. His literary interests specifically lie in the history and philosophy of science.

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One comment on “Supramolecular chemistry: Moving away from synthesis and toward design

  • What a lovely read. I love the concepts in this sadly I don’t do chemistry any more so alot of it doesnt make sense however has inspired me to get my books out again :)


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