Supramolecular chemistry is the science of non-covalent interactions between molecules. The formation and destruction of weak bonds (such as hydrogen and coordination bonds, van der Waals forces, etc.) is a key component in the processes of forming self-organising systems, including living organisms. Knowing how such systems work allows scientists to design complex materials and machines consisting of just a few molecules. Over the several decades of its existence, supramolecular chemistry has become an interdisciplinary science, whose success is the most important condition in developing such applied fields as medicine, nanotechnology, and material science.
We know from school that chemistry is a science that studies the elements (atoms), their molecules, and their transformations. Atoms in molecules and crystals are held together by a strong (covalent or ionic) bond. Climbing the matter organisation ladder, we inevitably face the question of how molecules interact with one another.
Since the 19th century, chemists have been interested in complex chemical (primarily bioorganic) compounds. With improvements in synthesis methods, scientists have been tempted to recreate or imitate biological processes, such as that of an enzyme interacting with a substrate. This led to the emergence of a new discipline in the late 20th century: 'chemistry beyond the molecule' or supramolecular chemistry, the objects of which are supramolecular formations: supermolecules and molecular assemblies.
Jean-Marie Lehn. Source: www.chemistry.msu.edu
The term 'supramolecular chemistry' was coined in 1969 by the French scientist Jean-Marie Lehn, to whom, incidentally, the term 'supermolecule' also belongs (1-3). Jean-Marie Lehn was awarded the 1987 Nobel Prize in Chemistry together with the Americans Charles Pedersen and Donald Cram for the production of compounds that mimic the function of enzymes. This award, in fact, 'ratified' a new branch of science (4). Lehn defined supramolecular chemistry as "the chemistry of intermolecular bonds". Just as molecules are created by joining atoms through covalent bonds, supramolecular structures are built by non-covalent (van der Waals, electrostatic, hydrophobic) interactions, as well as by the formation of hydrogen and coordination bonds. In general, such bonds are much weaker than covalent bonds (on average, by 1-2 orders of magnitude) (2-3). How then do supercompounds maintain integrity?
It's all about the number of these connections. A gecko does not fall from the ceiling due to millions of van der Waals interactions between the hairs on its paws and the surface (3). Just like the Lilliputians bound Gulliver, many weak bonds hold the structure of supermolecules. Such a setup makes supramolecular structures more labile and flexible, which brings them closer to real biological systems that can quickly and reversibly respond to external influences (3,5).
One may draw the following analogy: supramolecular chemistry is like molecular sociology. It does not look at individuals (molecules), but the collective and its characteristics. The properties of a collective are not just the sum of its members' properties, they also depend on the nature of the interaction between members and on external conditions. Supramolecular structures are thus the result of not only additive, but also cooperative interactions. In other words, the whole here is greater than the sum of its parts (3).
The first supramolecular structures to be studied (and the simplest) are the so-called 'host-guest' complexes. A 'host' is usually a large molecule with a cavity; and a 'guest' is a small molecule or ion (2-6). The host invites a specific guest, and not just any: this reflects the selectivity of molecule interaction. The guest is held in the 'home' of the host due to weak bonds, or simply mechanically. The home becomes a prison cell (hence the name of some supramolecules - carcerands from the Latin carcer - 'prison', and clathrates, from the Latin clathratus - 'with bars, latticed'). The first artificial guest-host systems were crown ether complexes with alkali metal ions. Charles Pedersen accidentally synthesised crown ethers, for which he received the Nobel Prize (2-4). Interestingly, clathrates have been used in practice for quite some time. For example, in the processing of crude oil, unwanted paraffins are removed from gasoline by being trapped in clathrate gratings (3).
Since the 1960s, in parallel with the development of systems capable of selectively recognising and binding certain substances, scientists have sought to create 'truly' mechanically connected complexes in which molecules would adhere to each other without the direct interaction of atoms. It was in 1983 that a French scientific group headed by Jean-Pierre Sauvage developed a technique for the directed production of catenans (from the Latin catena — 'chain') — a system of two or more organic molecules connected like the links of a chain without any chemical bonds (5,7). Until recently, the number of links never exceeded seven. However, in 2017 scientists announced that a complex of 130 mechanically linked molecules had been obtained (8). Sauvage's revolutionary method allowed him, together with another specialist in this field, James Fraser Stoddart, to create molecular versions of such cultural symbols as the trefoil knot, Solomon's knot and Borromean rings (5,7). The synthesis of catenanes was the first step in the design of molecular machines — devices a thousand times smaller than the diameter of a human hair (7).
Another important event in this field was the creation by Stoddart's team in 1991 of rotaxanes — supramolecular complexes in which a macrocyclic compound (a ring-shaped molecule) is worn on an axis molecule. The 'dumbbell-like' form of the axis molecule prevents the ring from slipping off (5,7). Stoddart managed to control movement of the macrocycle along the axis through changes in the external environment. As a result, in 1994, the first molecular machine appeared (7,9). Furthermore, molecular lifts based on rotaxanes were created, capable of rising to a 'height' of 0.7 nm, as well as artificial 'muscles' and even a computer chip with 20 kB of memory (7).
The next breakthrough in supramolecular chemistry was the replacement of translational motion in molecular machines with a constant motion in a given direction. In 1999, the Dutch scientist Bernard Feringa created the first molecular motor. This motor was not fast, but in 2014 scientists achieved rotation at a speed of up to 12 million revolutions per second (7). In 2011, the Feringa research group built an all-wheel-drive «nanocar»: a molecular chassis held four motors that functioned as wheels (10,11). France even held the world's first Nanocar race in 2017.
Example of a molecular car structure
It is not surprising that Sauvage, Stoddart and Feringa were awarded the Nobel Prize in Chemistry for their work in 2016 (12). Researchers all over the world use the structures and methods created by the Nobel laureates. One of the most striking examples of such structures is a rotaxane-based molecular robot that can capture and bind amino acids (11).
Despite the appeal of creating works of chemical art such as molecular racing cars and nanodevices, from the outset supramolecular chemistry has sought to recreate real biological processes in artificial systems. After all, we can say that all wildlife consists of supramolecular structures (6). Enzymes, which play a part in practically all reactions in living organisms, are ideal host molecules that interact only with a specific guest substrate. Various cellular receptors respond only to certain substances. Although complex in its structure, the simplest example of a supermolecule in the body is DNA, in which two strands of nucleotides are complementarily linked by numerous hydrogen bonds, simultaneously acting as both guest and host. The best existing supramolecular complexes are living systems, which is ultimately to say, us ourselves. This fact makes the development of new supramolecular structures that mimic biological systems extremely sought-after in the field of biology and medicine (6).
The protein kinesin transports membrane vesicles along microtubules in a cell
An extremely promising and interesting area for development in supramolecular chemistry is the study and reconstruction of the spontaneous formation processes of supramolecular assemblies, so-called 'self-organisation' and 'self-assembling' (2-3,5). In this process, molecules or small molecular structures join independently, forming intricate and much larger supramolecular complexes.
An example of work of nano-art. For scale, the figure of a dancer is placed on a pin. Source: CNN
Molecular robots, self-assembling molecular structures, molecular knots – this is all extremely interesting, but the natural question arises: why do we need all of this? At first glance, advanced achievements in the field of supramolecular chemistry seem more like toys for scientists. In fact, this field of science is, first and foremost, of great importance for fundamental research. It helps us better understand the nature of intermolecular interactions and self-organising systems, and more efficiently study the mechanisms of some phenomena and nonequilibrium systems (to which all living systems belong) (5). Thus, the effects and characteristics of ultrahigh dilutions of various substances can be the result of stable supramolecular structures forming (13), and structured water can contribute to the formation of supramolecular polymers (14). American scientists recently demonstrated that self-assembly of complex supramolecular structures in an aqueous medium under artificial conditions is possible using a three-dimensional organic catenane (15).
As for the practical application of the 'fruits' of supramolecular chemistry – this is currently new materials with controllable properties. For example, scientists have proposed a new approach to the selective purification and extraction of substances using smart materials (3,5,7). Gels already exist that expand or contract under the influence of light or chemicals. Such materials can act as photosensors and chemosensors (3,7). A self-repairing Nissan Scratch Shield iPhone case made of polirotaxan was released in 2012, which can even protect the phone from a hammer blow (11). A potential application of supramolecular structures and materials in biology and medicine is the directed transport of biologically active substances into organs and tissues through molecular machines, the development of novel drugs (for example, drugs against antibiotic-resistant bacteria), and the use of new materials in regenerative medicine (3,6,16).
The prospects for using supramolecular systems are probably not yet fully understood by scientists. Advances in supramolecular chemistry are at approximately the same stage today as advances in electrical engineering were in the 1930s. At that time, researchers proudly demonstrated rotating crank levers and wheels in front of crowds of onlookers, unaware of how tomorrow's science would transform the world.
1. Steed J.W., Atwood J.L. Supramolecular chemistry. - Moscow.: Academkniga, 2007.
2. Lehn, J. (1993). Supramolecular chemistry. Science, 260 (5115), 1762-1763.
3. Desiraju, G. R. (2001). Chemistry beyond the molecule. Nature, 412 (6845), 397-400.
4. The Nobel Prize in Chemistry 1987 was awarded jointly to Donald J. Cram, Jean-Marie Lehn and Charles J. Pedersen "for their development and use of molecules with structure-specific interactions of high selectivity."
5. Mattia, E., Otto, S. (2015). Supramolecular systems chemistry. Nature Nanotechnology, 10 (2), 111–119.
6. Ariga, K. (2016). Supermolecules. Biomaterials Nanoarchitectonics, 25–40.
7. Fernholm A. The Nobel Prize in Chemistry 2016. Popular science background. https://www.nobelprize.org/uploads/2018/06/popular-chemistryprize2016-1.pdf
8. Wu, Q., Rauscher, P. M., Lang, X., Wojtecki, R. J., de Pablo, J. J., Hore, M. J. A., & Rowan, S. J. (2017). Poly[n]catenanes: Synthesis of molecular interlocked chains. Science, 358 (6369), 1434-1439.
9. Bissell, R. A., Cordova, E., Kaifer, A., Stoddart, J. F. (1994). A chemically and electrochemically switchable molecular shuttle. Nature, 369 (6476), 133-137.
10. Kudernac, T., Ruangsupapichat, N., Parschau, M. et al. 2011. Electrically driven directional motion of a four-wheeled molecule on a metal surface. Nature, 479, 208–211.
11. Peplow, M. (2015). The Tiniest Lego: A Tale of Nanoscale Motors, Switches and Pumps. Nature, 525, 18-21.
12. The Nobel Prize in Chemistry 2016 was awarded jointly to Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa "for the design and synthesis of molecular machines."
13. Demangeat, J.L. (2013). Nanosized solvent superstructures in ultramolecular aqueous dilutions: twenty years’ research using water proton NMR relaxation. Homeopathy, 102 (2), pp. 87-105.
14. Dong, S., Leng, J., Feng, Y., Liu, M., Stackhouse, C. J., Schönhals, A., … Schalley, C. A. (2017). Structural water as an essential comonomer in supramolecular polymerization. Science Advances, 3 (11), eaao0900.
15. Li, H., Zhang, H., Lammer, A. et al. Quantitative self-assembly of a purely organic three-dimensional catenane in water. Nature Chem. 7, 1003-1008 (2015).
16. Webber, M. J., Appel, E. A., Meijer, E. W., & Langer, R. (2016). Supramolecular biomaterials. Nature Materials, 15 (1), 13–26.