Functional Supramolecular Systems
We need to thoroughly reconsider our views on the formation of supramolecular structures, says Bert Meijer. “Supramolecular structures are the result of a series of reaction steps, just like complex molecules are. That is why we should start thinking in terms of non-covalent synthesis, which implies that we need to develop synthetic methods, just like we do in classic organic synthesis.” But how? That is what the focus area on Functional Supramolecular Systems aims to find out.
Fortunately, there are two sources of inspiration that offer guidance, says Meijer. “The first is the immense body of knowledge that chemists have built over the past 150 years on how to make molecules. We know a lot about covalent organic synthesis and that allows us to create the most complex molecules we can imagine. But all these techniques and approaches are also very valuable to supramolecular chemistry. We can use those insights to develop methods for what I like to call non-covalent synthesis.” The second source of inspiration, says Meijer, is Nature itself. Living organisms are very skilled in constructing supramolecular structures that exhibit a desired functionality. “These structures contain all kinds of polymers and although we know a lot about covalent polymer synthesis, we don’t yet understand how Nature creates these highly functional polymer-based structures. Biological examples will offer clues on how we can apply the concepts used by Nature to develop synthetic analogues.”
Which brings us to self-assembly, Nature’s way of making what it needs. It is by now also the preferred approach of supramolecular chemists around the world. When asked why we actually need new methods,Meijer sighs and throws up his arms. “I know, everyone talks about selfassembly and self-organization and I understand that, because it sounds really attractive. But self-assembly is a deceptive term. It implies that everything just happens by itself and the only thing you need to do is put all the compounds together, give it a little shake and then sit back and wait until it’s done. But this means you completely rely on thermodynamics to deliver the final structure. The problem is that in this approach you will always end up with the outcome that is most favorable under those particular conditions. And that is not necessarily the structure you want.”
Listening to Meijer, one gets the impression that chemists need to take back control and not simply let the system run its course and accept whatever it delivers. But what can chemists do to influence and steer a self-assembling system in the right direction? “It starts by studying the fundamental mechanisms of the various reaction steps that together make up the assembly process. Each assembly step is a reaction step, just like we have in multistep covalent synthesis. I consciously use these terms, because I want to convince the field that self-assembly is a synthetic process. And if you understand the mechanisms that underlie the various steps, you can look for ways to promote or inhibit certain steps.” Although Meijer immediately admits that he doesn’t have a ready-made solution, he has a number of ideas on where to start. “So far, all the focus has been on thermodynamics, but the kinetics of these self-assembly processes have been largely ignored. Studying the kinetics is a must, because we all know that the kinetics determine the route towards a certain end product. And if a system has multiple routes available, you have to make sure that your desired route is, or becomes, the most favorable one. Otherwise your system will get stuck in a kinetic trap. The only way to do this is to study the kinetics of all the potential pathways and then devise a strategy to push the system towards the pathway of your choice. For covalent synthesis, these questions were already asked in the 1890s, but now we need to address them for non-covalent synthesis as well.”
This is just one illustration of the overall shift in thinking that Meijer advocates. The current view is that chemists actively make molecules, but they don’t ‘make’ supramolecular structures. These somehow just emerge from a completely autonomous process that is beyond our reach. “Of course, it would be great if we could just throw all the ingredients together and be done with it. That would also be very attractive for classic organic synthesis. Think about the very complex synthesis of vitamin B12.
Wouldn’t it be wonderful if you only had to put all the required atoms in a flask, shake it and that’s it. The strange thing is that nobody would even consider this to be possible for vitamin B12 or any other molecule. But somehow, when it we talk about supramolecular structures, the general feeling is completely different.”
Interestingly, Meijer adds, Nature - the field’s premier source of inspiration - is not taking the ‘throw it together and lean back’ -approach at all. “A perfect example are chaperones, which are needed to fold proteins into the right conformation. This is the only task of chaperones, these compounds serve a synthetic purpose. Another example is collagen. In the cell, the collagen filaments are formed with a little extra structure on the ends. Once the filaments exit the cell, these little structures are removed and then the filaments can start to assemble into larger fibrils. To me, those little structures are the equivalent of a protective group that we use in organic synthesis. They serve the same purpose and that is to control a reaction step in a larger synthetic process.”
In spite of all the fundamental knowledge we still need to gain, Meijer is optimistic that we will make substantial progress over the coming years. Moreover, it is imperative that we do, he concludes. “Because if we don’t, we will just keep on running into the same wall over and over again.”