Towards Adaptive Chemistry
Lehn, Jean-Marie
Molecular chemistry implementing reversible chemical bonds in molecules, and supramolecular chemistry, whose molecular components are held together by intermolecular interactions, may continuously change constitution by building block exchange. They define a Constitutional Dynamic Chemistry on both molecular and supramolecular levels. It takes advantage of dynamic constitutional diversity to allow for variation and selection in response to either internal or external factors to achieve adaptation, pointing to the emergence of adaptive chemistry. Lehn, J.-M., From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry, Chem. Soc. Rev. 2007, 36, 151. Lehn, J.-M., Perspectives in Chemistry – Steps towards Complex Matter, Angew. Chem. Int. Ed. 2013, 52, 2836.
 It's nice to be back in Lindow. Now, this is another setting, as the one I had been in last time. And it's quite nice one. I must say I prefer that perhaps to the more modern type of setup. Anyway, so let me tell you about some perspectives in chemistry. And now we are very interested in developing an area which we may call adaptive chemistry. We'll try to explain what it is about. Now, as you know, we have chemists who are supposed to be able to make molecules, to design them by using linking atoms to covalent bonds. Beyond that, there is an area which we have now developed for many years, which is super molecular chemistry, which deals with the way in which molecules interact. And three main functions were studied over the years. How do molecules recognize each other? We have a lot about that, because in biology, any function starts first with a recognition process. Then how do they react with each other? How can they carry each other through a membrane? And recognition is the basis of this. But we think a bit more about what happens beyond super molecular chemistry. What can we learn from it? It is quite obvious, but it was taken for granted for many years, that super molecular chemistry is a dynamic chemistry inasmuch as the pieces linked together by these non-covalent rather labile interactions, these pieces can exchange. And therefore, a super molecular object can undergo variation in constitution by exchanging its components. Now, this then led to the idea that in fact this is a dynamic chemistry which relies on non-covalent labile interactions to exchange the pieces. The next step was to see whether or not one can introduce these dynamic features residing in the constitution of the object to molecular structures. And indeed, this can be done if a molecule is constituted by atoms linked through non-stable bonds, bonds which can break and then exchange also pieces. That was something a bit disturbing, because when you make molecules, you want them to be stable. And if they're not stable, you usually cool them down in a fridge or whatever just to keep them from breaking up. But you can ask the question, let's turn the question around, and say what would happen if we now make molecules which do the reverse, which exchange their pieces? And this then led to the idea that there must be perhaps an interest in studying a dynamic covalent chemistry. You can then combine these two under the same title, the same roof, and calling this a dynamic chemistry residing in the constitution of the chemical object. That chemical object can be molecular or it can be super molecular. So it is a dynamic chemistry based on the constitution of the chemical object. And this opens then the possibility that your entities may be able to adapt, to open the possibility of an adaptive system where the system might respond in its constitution by exchanging its components to stimuli of physical nature or to chemical effectors. And that opens possibly the road to an adaptive chemistry. Now, this constitutional dynamic chemistry, what is it good for? First of all, it makes a mess. It makes a mixture. But you may call now a library, of course a much nicer name, in older times who called that a mess and you throw it away. But now we think that it might be very interesting to study the diversity generated and indeed this generates diversity on both the super molecule and the molecular level and then makes possible something which is also a term which perhaps for biologists is more common, but which is interesting, the fact that you can select pieces, you can select different constitutions of interest for biologically active substances, discovery of biological substances which are active, and implementing dynamics in nanodevices and also perhaps making dynamic materials, like dynamic polymers. I will only discuss two parts of it, the biologically active substances and the dynamic materials. First you have to choose a reversible chemical reaction. There are many. We have mostly studied an emblematic one which is the condensation of a carbonyl with an NH2 giving an emin. That's a nicely reversible reaction. It's not so simple as it looks on the screen, in fact, but it is a nice one which one can study and there are good reasons for that, that both organic molecules bearing it and of course bio molecules. Other reactions can be studied. The group of Jeremy Sanders in Cambridge has studied mostly disulfide formation exchanged by making disulfide bonds and exchanging the pieces. So, immune formation. This is just the framework, just the basic reaction, but I would like to understand the concepts behind. That's just the workhorse, so to say. So, how can you come to searching for biologically active substances by using this kind of principle? If you go back to the image of Emil Fischer of the key and the lock, how can you make a key for biological lock? This would be the key, would be the biologically active substance for binding to the biological target, the lock. So, the design chemistry would be to make one key the right one for the lock. That may be difficult because you have to know the lock. You have a lot about x-ray crystallography and also about dynamics. You have to know the lock, you have to build the key, you have to test it. Another approach is to try a sort of random means of generating a lead substance by making very many keys, just trying them out and hoping that you will find one which may have some interesting activity and then you can improve on it. But this one, of course, is not teaching you much about how molecules recognize each other. So, how can you combine the information which is present in the recognition process, one key for the right one, or the possibility to study many, many molecules, sort of a computer-tool approach? This would be nice if you can do a dynamic combinatorial which relies on the generation of fragments, I come back to that. And this would then combine combinatorics, that means the way in which you can recombine the pieces so as to generate a very high diversity and informatics the way in which these things interact, the information stored in the molecules and which leads to these recognition processes. Just one slide to illustrate that, because I would like to go to other things. If these are the components of different structures, different types of structures, with here a point, this black dot, which is a functional group which can undergo reversible connection. When you mix those together, you generate an interconverting set of constituents. You have access through this reversible reaction to all the possible combinations of the pieces. Now, this gives a complex mixture of entities all the time interconverting. So what can you do then? You lose a basic law of thermodynamics, which is that you add the receptor and the receptor should best bind the combination which is the most suitable for this receptor site. And that means that the lock and key will be sort of a dynamic key which the lock will then select and lead to the most stable binder. In other words, the lock does the driving, the lock assembles its own key. In fact, this can be used then for trying to track discovery processes. It has been used and applied for discovering enzyme inhibitors and also for looking at substrates for biological artificial or biological receptors. I don't want to go more into that, but the principle has been demonstrated in a number of cases. Now, I would like to switch to what you can do in the field of materials. Dynamic materials look like something also one of sort of a thing which you might not like to do because you don't want to make really materials which fall apart. But they maybe have properties, perhaps, which are different from static materials because they might be self-healing, responsive, adaptive materials. Let's look at a class of materials, dynamic polymers, which we like to call dynamers. These dynamic polymers can be of two types. One type is on the molecular level, if this is a monomer with two functional groups at each end of a given spacer. And this is another monomer with two functions at the end of a spacer. And if these two functional groups are complementary, complementary meaning that they can undergo a reversible reaction, then you get a chain which is dynamic in its constitution because these connections can break reversibly and that would then be a molecular dynamic polymer. On the other hand, if it is not a polygondensation but a polyassociation through interactions, then these entities, the red one, are interaction complementary interactional groups undergoing molecular recognition. And then it's a super molecular non-covalent dynamic polymer. Let's have a quick look at the super molecular polymer chemistry. This is a field which developed quite a bit over the last 30 years or so and it was a bit difficult to have it to convince polymer chemists at the beginning but now it's well accepted and that will just illustrate a point. What can one do on the basis of the super molecular polymer chemistry? How does it build up? I mentioned here the date when we published the principle, the first time we published that where the principle was introduced in 1990 because I need this date 1990 in a moment, as you will see. So the principle is simple. I just quickly mention it. You have a spacer, you have two end groups. These end groups here are hydrogen bonding groups undergoing donor, acceptor donor of hydrogen bond formation and the complementary to DAD is then ADA, acceptor donor acceptor, so that if you mix this component with this component, the result is the formation of a super molecular polymer main chain where the polymeric entity is linked, where the units are linked together by forming three hydrogen bonds between the components. Just to illustrate that there is a big difference in material properties, these two are solids and that's a liquid crystal. I don't want to go into more details, but this was just an illustration of the principle of making super molecular main chain polymers, which then was developed a lot, especially by Bert Meyer in Eitoven, where a lot of very nice work was done to develop the ideas and to make a range of compounds and materials also by a number of other groups. This is an electron microscopy picture showing that indeed the material has fibers which can connect together, I don't want to go more into the details. Why do I mention that? First of all, because it is a dynamic polymer, it is a polymer based on non-covalent interactions, but also to illustrate how long it can take to go from basic concept to an application. In 2003, one can look at the possibility to have self-healing materials. Let's have a look here. That's a transparent film which contains entities which are linked by non-covalent interactions. You can cut this film in two, superimpose the two ends, and then you press with your finger just for some time, not very quantitative, but you press with your finger and you can stretch and it sticks again. I have a movie for that, but I didn't want to show it, it takes a bit too much time just to get from one thing to the other one. But you can see this, you can stretch, and it has the mechanical properties almost the same as the starting film. This, the reason that it is not the same is probably that it was not pressed long enough and there was not a very quantitative way of doing things, but this just demonstrates that supermolecular polymer films are self-healing materials. Now, the other point of importance is in addition to having this practical material type of application, there is another possibility, and in 2013, in October of that year, I got an email from a small company saying, we have developed supermolecular polymer materials which are biocompatible. And what they had done is using supermolecular materials, this company Xeltis, has used this type of material to make cardiovascular implants. These cardiovascular implants were then used for the reconstruction of the heart of children who had a congenital cardiac malformation. It was indeed done, and here you see the first young girl who was implanted by Leo Boqueria, he's a cardiovascular surgeon at the Bakulev Scientific Center for Cardiovascular Research in Moscow. This was in 2013, it's now almost four years later, and she's fine. Many more children have now been implanted, at least 10, but I haven't followed all of it, so more than that. So that is, of course, for when you do basic research, it's great satisfaction to see that some of the principles introduced many years earlier, finally, came to a material which is now present and used in surgery for children. This has now been developed also by the same company to make a heart valve, which is shown here, which was implanted in July 2016, and which, for the moment, is also going well. They tell me that it's really a big change in surgical practice. Now, this is just about supermedical polymers, and as I said, this field has now developed very much, and there's a lot of work going on in the area. What about now making dynamic polymers which are covalent, where the connections between the pieces are covalently reversible? Then you would simply think of doing something which any chemist is sort of a very simple kind of thing to do, is to dye carbonyl, the dye amine, you mix them together, and you get a polyemine. No big deal, and you can make them for polyemines, or you can use hydrazine to make polyazole hydrazones. This is just something which, for a chemist, is quite a normal thing to do. So now, what can one do with this type of polymers? What can one use them for? Are they interesting, or are they just some kind of idea which doesn't need to match? If you make a film of dynamic polymers which can undergo dynamic component recombination, you can superimpose these two films. And let's now look at A and B as two components of the film. A might be a dye amine. B might be a bis carbonyl. So A, B, A, B, they are all together, forming that dynamic polymeric chain. You can then make another film which has another dye amine, A prime, and another bis carbonyl compound, B prime, and you make then the chain, A prime, B prime, A prime, B prime. Now you superpose the two films. What would happen? What can happen? This connection is in principle dynamic. And then, of course, it can disconnect and recombine with the film below. In other words, A can now combine with B prime, and A prime can combine with B. That means that you can generate inside your material the two new combinations which did not exist before. And that can be quite interesting, because they may have other properties. They may change the property of the material itself in a way which is a dynamic way. Let's assume these are the imines, but they can be other functions of that type. And so how can one make use of it? Several ways have been tried and have been implemented. One is to change the mechanical properties of the objects. Another one is to change the hydrophilicity or hydrophobicity. But the best illustration is by looking at optical properties, because you see it. And these optical properties can be changed for such a material by just recombination of the pieces inside the film. You can hope for generating changes in color and in fluorescence of these dynamic polymers. How? Again, you have a film AB. I go back to the same nomenclature. You have a film A prime B prime. You superimpose just a part of it, for instance, the corner. At that place where it's superimposed, what I just showed on the previous slide can happen. Recombination of the components so as to generate A, B prime, and A prime B. A combining with B prime and A prime combining with B. If one of these two combinations has a color, it will be generated. You will see it. Or if it has a fluorescence, you will see it also. In other words, you may optically see whether the recombination, which I'm talking about, has occurred. Now, this was a collaboration with Mitsui Chemicals. And they were sending collaborators, from Japanese collaborators from their plant in Chiba, to my lab. So we were developing the basic results in that. And they were interested in potential applications. So my Japanese coworkers then, they like these nice little pictures. This is a cat head, where the head and the ears is AB. Inside of the ears, the eyes and the mustache is A prime B prime. You superimpose. And then you just let the reaction go. You help it by heating. You get color and you get fluorescence. Only when it's superimposed. That shows, of course, that the exchange works. That there is indeed a recombination at the interface between the two films. It also indicates that potentially it is possible to use, for instance, a heating laser to write at the interface between two films. Or if you make a stack of the films, you might be able to write in three dimensions. We have not tried that, but I'm sure there might be bright engineers around the world making very good films and making very nice ways of handing them, superimposing them, and trying them out for this type of purpose. So making them, therefore, materials which are responsive to external stimuli. This can be applied to the basic classes of biopolymers. We have done it in all three cases, but it's just scratching the surface for the moment. One can make dynamic nucleic acids where the components bearing a nuclear base, which can be connecting together to make a strand, but can apply to dynamic peptoids. It's not really peptide because you need to introduce the reversible function, where, for instance, here, the hydrosyth of an amino acid can be combined either with a function contained on the other side of the amino acid or with a complementary type of amino acid. And then you get a peptoid where there are reversible connections and which then may exchange amino acid-like pieces. That is also quite interesting because if one of these combinations, which is formed by exchange, has a conformation which is particularly stable, that's the one you should generate. Finally, you can also do it with sugars, carbohydrates, and make dynamic like odenomers, like, for instance, this one, which is an oligoarabino-theranos, where you have here a reversible combination and making a dynamic glycodynamic chain. These three areas are still, I think, of much interest. Of course, you can think of combining the amino acid subunit to a sugar subunit to make mixtures between glycosidic and peptoid type of entities. And you can also think of course with dynamic nucleic acids. So I think there's a lot of work to be done there and maybe also for interesting biological and maybe even drug applications generating combinations which might have interesting bindings to membrane surfaces, to just to trapping molecules and so on. I can imagine many things, but a lot of work is involved. And for instance, for denoting peptoids, Anahirsh is now continuing that work. Now, what about this adaptive chemistry then? Adaptive chemistry is to make entities which can undergo variation in their constitution, not shape, constitution, depending on some agent, like the medium, the phase change, physical effector, can be heat, can be pressure, can be electric field, chemical effector, and even a change in conformation. These type of changes are included in a network. I come back to what I need to a network. I just mentioned it here. And make it to adaptive chemical systems. I would like to illustrate that by the following way. Suppose you have these two monomers which have a strong, a big hydrophobic core and a side chain which makes them water soluble. This is a di-carbonil. That's a dihydrozyte. So if you mix those two, what do you get? You get the polycondensation. And we had independently studied that you get a polymer, which is quite an interesting one, which is characteristic inasmuch as hydrophobic effects in water will try to minimize contact between the hydrophobic core and the aqueous solution, the aqueous phase. Therefore, putting the core inside a rigid rod and having the chains which make it soluble in water sticking out. OK. In itself, it's an interesting polymer. But the interesting question you can then ask, is you now ask the system to solve a question, to give an answer to a question. The question is, let's mix these two where you have a small hydrophobic core and a large hydrophobic core. And now ask this other component to choose between the two, which will be included in the dynamic polymer. If you work in water, you would expect, and that goes to have perhaps already guessed, that you will still get the same. And this will just stay out because the system, somewhat dynamically, will push towards excluding contacts between water and the hydrophobic core. And indeed, that is what happens. You have a selective polymerization of this with that, despite the presence of the other one. But then you can do a counter experiment just to show this if this is correct. If you go progressively from pure water to organo-water mixtures, you should lose the selectivity. And indeed, when you add acetonitrile, you add 80% acetonitrile added. You have random incorporation. So you have lost this hydrophobic driving effects, which make the system select for one component and excludes the other one. So you have a component selection, which is based on exclusion of contacts between hydrophobic pieces of the molecule and water. Another case of interest is work done in collaboration with one of my colleagues, Paolo Samoé. It was much more had been done there. But let me just summarize one aspect related to what I'm telling you. Suppose you have this long chain of aldehyde, which deposits very well on a surface. And you mix it with these three diamines. You deposit that on a graphite surface, and you look at the STM pictures of what happens. If you look first at the solution, the phenyl-octane solution, what you find in that solution by NMR is simply mono-E-means, not diamines, and only 1% to 5% to PC means, and a mixture of all three, which is what you expect. Just a statistical mixture, but only a simple single mean. Now you deposit that on a surface. What you now have is only one compound and only PC main. Because that's the one which adsorbs best. That means adaptation to the surface pushes the system to generate here to drive a complete reaction, driving the reaction to completion, and selecting for the best, most stable PC main. That means that adaptation occurs to the adsorption to the surface. It's adsorption forces, which leads to the selection of the right components. And it's a self-organization on the surface, which leads to it. It's interesting that this is perhaps also interesting at the origin of life scenarios. Because if things deposit, if selection can occur simply by deposition and interactions, there could be an interesting contribution there to select D by adsorption forces. Now let me come to this notion of networks. This notion of networks is that you would like to try to see if these entities, they really talk to each other. You have a mixture where they exchange components. So each of them talks to the other one. Let's look at the simplest case. If you have, again, I come back to this new microtrax, A, A prime, and BB prime, which can react with each other to generate AB, AB prime, A prime, B, A prime, B prime. These four exchange their pieces. And therefore, they form a network. And this simple network is, in this case, the simplest you can imagine, a square. You can then put the four constituents at the corners of the square and look at their relationships. On the edges, the constituents have a component in common. AB has in common A with AB prime and B with A prime B. So if AB increases for some reason, it does it at the expense of these two, which means these are antagonists. On the other hand, on the diagonals, the relationship is agonistic. If AB increases, it liberates A prime and B prime, which can make more A prime, B prime. Therefore, you have two types of relationships, antagonistic on the sides of the square, and agonistic on the diagonals. Now, what can I do with this? Of course, in a very, we have now more complicated networks with up to nine components. And this could be an interesting, more complicated relationship there, but let me look just at the simple one. Because we can act on one of those thoughts, did one of those constituents, and see what how the other ones respond. And this would then be an adaptive chemical network, the chemical network, which will respond to agents. So let's have a look at, first of all, a very simple illustration, and then a somewhat more complicated one to conclude. Suppose you have a statistical mixture of these four constituents, where AB have what I said, A are the altitudes, B are the hydrosites, and you have these four constituents. Now, you treat with a metal. In among those four, there is one we should bind the metal very well, which is the one which has NNO3 coordination sites. If you add some base, it will ionize the NH and have a more stable complex. The result is, as you add the metal to this mixture of four, you get only two at the end, because you strongly amplify AB by binding of the metal. But as the consequence, A prime, B prime will also be amplified. I come back to that, because I find that is one of the most important conclusions. So you have amplification of one constituent by driving the system with the metal. Yeah. So you have these four constituents, and you get this. And then you amplify, and you get this amplification of AB, and also of A prime, B prime. What does that mean? That means that you have an adaptation to the addition of the metal. And that you have what I call an agonist amplification. In other words, the fittest for binding the metal amplifies also the unfittest. Unfittest for that property, but maybe good for something else, which might indeed be interesting, because the unfittest may have some other properties. Let me just conclude rapidly. In view of time, I will be short. But just to illustrate an important driving force, which is self-organization, organization of system, which leads to a higher organization that is starting material. It is well known that Guanines form a Guanine G-quartet, and they form then a gel. Now a gel is more organized than a solution. So what can you do with these forces of gelification of this organization? You can take a set of components. One of them be having a guanosine residue, and the other ones having the connection possibilities, with this NH2 here, periodoxal or sulfonated benzaldehyde, and another piece, which is derived from alanine. So you mix that, what do you get? So this is here from Cering. What you get here is that you get now a gel. In the solution, which is included in this gel, in the pieces which are still a solution, you have three components. In the gel, you have only one. The one, of course, is formed as a gel. But interesting thing is not only that. That is quite obvious, that the one is formed as a gel is the one which contains the guanosine, the guanine residues. The one is formed as a sol are the others. But you can see that the proportions are such that AB is strongly amplified by gel formation. As a consequence, A by pre-prime is also strongly amplified. Again, therefore, you have an amplification of the constituent, which leads to the organized state. Whereas the agonist, which is the counterpart, which is in the solution, is also amplified. So you have a self-organization. You have a selection of components, either self-organization pressure. To summarize, in the beginning, you have statistical distribution. You let gel formation occur. You have amplification of the one which forms a gel and the one which does certainly not form a gel, the least able to form a gel. This is a self-organization driving force. And therefore, you can say that self-organization drives component selection in a way to generate the best for making an organized state. And of course, amplifies also its agonist. This adaptation results in adaptation under the pressure of self-organization. Again, stabilizing the fittest here, not by a metal line, but by self-organization forces also drives the amplification of the unfittest for that, the most soluble one. And this is perhaps also interesting again for pre-biotic origin of matter. Because if a system is such that, it may select for a more organized state, it will select the pieces it needs to form the more organized state. And this before any selection can occur on biological nature, this is a purely chemical way of proceeding. So let me just summarize. As chemists, we have to start with molecules. On basis of molecular chemistry, we can then develop a supramolecular chemistry, which leads to organized entities, which then are dynamic or can be made dynamic. For instance, when covalent, you have to make them dynamic, then they can become adaptive. And that is now the thing which you are mostly interesting, making systems which are adaptive, which respond to different type of forces, like crystallization, like vaporization, like inference of metal ions, all like. And for the most intriguing one is under the pressure of self-organization to lead to more complex states of matter. I think in the future, having this evolution of chemistry, if I could say it's an evolutionary chemistry even, having forces which lead to more and more complex states by themselves, selecting the more complex states, the more organized states, by selecting the right pieces. I hope that is one of the perspectives for chemistry. Thank you very much. Thank you. Thank you. Thank you. Thank you.
 It's nice to be back in Lindow.  Now, this is another setting, as the one I had been in last time.  And it's quite nice one.  I must say I prefer that perhaps to the more modern type of setup.  Anyway, so let me tell you about some perspectives in chemistry.  And now we are very interested in developing an area which we may call adaptive chemistry.  We'll try to explain what it is about.  Now, as you know, we have chemists who are supposed to be able to make molecules,  to design them by using linking atoms to covalent bonds.  Beyond that, there is an area which we have now developed for many years,  which is super molecular chemistry, which deals with the way in which molecules interact.  And three main functions were studied over the years.  How do molecules recognize each other?  We have a lot about that, because in biology,  any function starts first with a recognition process.  Then how do they react with each other?  How can they carry each other through a membrane?  And recognition is the basis of this.  But we think a bit more about what happens beyond super molecular chemistry.  What can we learn from it?  It is quite obvious, but it was taken for granted for many years,  that super molecular chemistry is a dynamic chemistry inasmuch  as the pieces linked together by these non-covalent rather labile interactions,  these pieces can exchange.  And therefore, a super molecular object can undergo variation in constitution  by exchanging its components.  Now, this then led to the idea that in fact this is a dynamic chemistry  which relies on non-covalent labile interactions to exchange the pieces.  The next step was to see whether or not one can introduce these dynamic features  residing in the constitution of the object to molecular structures.  And indeed, this can be done if a molecule is constituted  by atoms linked through non-stable bonds,  bonds which can break and then exchange also pieces.  That was something a bit disturbing,  because when you make molecules, you want them to be stable.  And if they're not stable, you usually cool them down in a fridge or whatever  just to keep them from breaking up.  But you can ask the question, let's turn the question around,  and say what would happen if we now make molecules which do the reverse,  which exchange their pieces?  And this then led to the idea that there must be perhaps an interest  in studying a dynamic covalent chemistry.  You can then combine these two under the same title, the same roof,  and calling this a dynamic chemistry residing in the constitution of the chemical object.  That chemical object can be molecular or it can be super molecular.  So it is a dynamic chemistry based on the constitution of the chemical object.  And this opens then the possibility that your entities may be able to adapt,  to open the possibility of an adaptive system  where the system might respond in its constitution  by exchanging its components to stimuli of physical nature or to chemical effectors.  And that opens possibly the road to an adaptive chemistry.  Now, this constitutional dynamic chemistry, what is it good for?  First of all, it makes a mess.  It makes a mixture.  But you may call now a library, of course a much nicer name,  in older times who called that a mess and you throw it away.  But now we think that it might be very interesting to study the diversity generated  and indeed this generates diversity on both the super molecule and the molecular level  and then makes possible something which is also a term which perhaps for biologists is more common,  but which is interesting, the fact that you can select pieces,  you can select different constitutions of interest for biologically active substances,  discovery of biological substances which are active,  and implementing dynamics in nanodevices and also perhaps making dynamic materials,  like dynamic polymers.  I will only discuss two parts of it, the biologically active substances and the dynamic materials.  First you have to choose a reversible chemical reaction.  There are many.  We have mostly studied an emblematic one which is the condensation of a carbonyl with an NH2 giving an emin.  That's a nicely reversible reaction.  It's not so simple as it looks on the screen, in fact,  but it is a nice one which one can study and there are good reasons for that,  that both organic molecules bearing it and of course bio molecules.  Other reactions can be studied.  The group of Jeremy Sanders in Cambridge has studied mostly disulfide formation  exchanged by making disulfide bonds and exchanging the pieces.  So, immune formation.  This is just the framework, just the basic reaction,  but I would like to understand the concepts behind.  That's just the workhorse, so to say.  So, how can you come to searching for biologically active substances by using this kind of principle?  If you go back to the image of Emil Fischer of the key and the lock,  how can you make a key for biological lock?  This would be the key, would be the biologically active substance  for binding to the biological target, the lock.  So, the design chemistry would be to make one key the right one for the lock.  That may be difficult because you have to know the lock.  You have a lot about x-ray crystallography and also about dynamics.  You have to know the lock, you have to build the key, you have to test it.  Another approach is to try a sort of random means of generating a lead substance  by making very many keys, just trying them out and hoping that you will find one  which may have some interesting activity and then you can improve on it.  But this one, of course, is not teaching you much about how molecules recognize each other.  So, how can you combine the information which is present in the recognition process,  one key for the right one, or the possibility to study many, many molecules,  sort of a computer-tool approach?  This would be nice if you can do a dynamic combinatorial  which relies on the generation of fragments, I come back to that.  And this would then combine combinatorics,  that means the way in which you can recombine the pieces  so as to generate a very high diversity and informatics  the way in which these things interact, the information stored in the molecules  and which leads to these recognition processes.  Just one slide to illustrate that, because I would like to go to other things.  If these are the components of different structures, different types of structures,  with here a point, this black dot, which is a functional group  which can undergo reversible connection.  When you mix those together, you generate an interconverting set of constituents.  You have access through this reversible reaction to all the possible combinations of the pieces.  Now, this gives a complex mixture of entities all the time interconverting.  So what can you do then?  You lose a basic law of thermodynamics, which is that you add the receptor  and the receptor should best bind the combination  which is the most suitable for this receptor site.  And that means that the lock and key will be sort of a dynamic key  which the lock will then select and lead to the most stable binder.  In other words, the lock does the driving, the lock assembles its own key.  In fact, this can be used then for trying to track discovery processes.  It has been used and applied for discovering enzyme inhibitors  and also for looking at substrates for biological artificial or biological receptors.  I don't want to go more into that, but the principle has been demonstrated in a number of cases.  Now, I would like to switch to what you can do in the field of materials.  Dynamic materials look like something also one of sort of a thing which you might not like to do  because you don't want to make really materials which fall apart.  But they maybe have properties, perhaps, which are different from static materials  because they might be self-healing, responsive, adaptive materials.  Let's look at a class of materials, dynamic polymers, which we like to call dynamers.  These dynamic polymers can be of two types.  One type is on the molecular level, if this is a monomer with two functional groups  at each end of a given spacer.  And this is another monomer with two functions at the end of a spacer.  And if these two functional groups are complementary, complementary meaning  that they can undergo a reversible reaction, then you get a chain  which is dynamic in its constitution because these connections can break reversibly  and that would then be a molecular dynamic polymer.  On the other hand, if it is not a polygondensation  but a polyassociation through interactions, then these entities, the red one,  are interaction complementary interactional groups undergoing molecular recognition.  And then it's a super molecular non-covalent dynamic polymer.  Let's have a quick look at the super molecular polymer chemistry.  This is a field which developed quite a bit over the last 30 years or so  and it was a bit difficult to have it to convince polymer chemists at the beginning  but now it's well accepted and that will just illustrate a point.  What can one do on the basis of the super molecular polymer chemistry?  How does it build up?  I mentioned here the date when we published the principle,  the first time we published that where the principle was introduced in 1990  because I need this date 1990 in a moment, as you will see.  So the principle is simple.  I just quickly mention it.  You have a spacer, you have two end groups.  These end groups here are hydrogen bonding groups  undergoing donor, acceptor donor of hydrogen bond formation  and the complementary to DAD is then ADA, acceptor donor acceptor,  so that if you mix this component with this component,  the result is the formation of a super molecular polymer main chain  where the polymeric entity is linked,  where the units are linked together by forming three hydrogen bonds  between the components.  Just to illustrate that there is a big difference in material properties,  these two are solids and that's a liquid crystal.  I don't want to go into more details,  but this was just an illustration of the principle  of making super molecular main chain polymers,  which then was developed a lot,  especially by Bert Meyer in Eitoven,  where a lot of very nice work was done to develop  the ideas and to make a range of compounds and materials  also by a number of other groups.  This is an electron microscopy picture showing that indeed  the material has fibers which can connect together,  I don't want to go more into the details.  Why do I mention that?  First of all, because it is a dynamic polymer,  it is a polymer based on non-covalent interactions,  but also to illustrate how long it can take  to go from basic concept to an application.  In 2003, one can look at the possibility  to have self-healing materials.  Let's have a look here.  That's a transparent film which contains entities  which are linked by non-covalent interactions.  You can cut this film in two,  superimpose the two ends,  and then you press with your finger just for some time,  not very quantitative, but you press with your finger  and you can stretch and it sticks again.  I have a movie for that, but I didn't want to show it,  it takes a bit too much time  just to get from one thing to the other one.  But you can see this, you can stretch,  and it has the mechanical properties  almost the same as the starting film.  This, the reason that it is not the same is probably  that it was not pressed long enough  and there was not a very quantitative way of doing things,  but this just demonstrates that  supermolecular polymer films are self-healing materials.  Now, the other point of importance  is in addition to having this practical  material type of application,  there is another possibility,  and in 2013, in October of that year,  I got an email from a small company saying,  we have developed supermolecular polymer materials  which are biocompatible.  And what they had done is using supermolecular materials,  this company Xeltis,  has used this type of material to make cardiovascular implants.  These cardiovascular implants were then used  for the reconstruction of the heart of children  who had a congenital cardiac malformation.  It was indeed done,  and here you see the first young girl  who was implanted by Leo Boqueria,  he's a cardiovascular surgeon  at the Bakulev Scientific Center  for Cardiovascular Research in Moscow.  This was in 2013, it's now almost four years later,  and she's fine.  Many more children have now been implanted,  at least 10, but I haven't followed all of it,  so more than that.  So that is, of course, for when you do basic research,  it's great satisfaction to see  that some of the principles introduced many years earlier,  finally, came to a material which is now present  and used in surgery for children.  This has now been developed also by the same company  to make a heart valve, which is shown here,  which was implanted in July 2016,  and which, for the moment, is also going well.  They tell me that it's really a big change in surgical practice.  Now, this is just about supermedical polymers,  and as I said, this field has now developed very much,  and there's a lot of work going on in the area.  What about now making dynamic polymers  which are covalent,  where the connections between the pieces  are covalently reversible?  Then you would simply think of doing something  which any chemist is sort of a very simple kind of thing to do,  is to dye carbonyl, the dye amine,  you mix them together, and you get a polyemine.  No big deal, and you can make them for polyemines,  or you can use hydrazine to make polyazole hydrazones.  This is just something which, for a chemist,  is quite a normal thing to do.  So now, what can one do with this type of polymers?  What can one use them for?  Are they interesting, or are they just some kind of idea  which doesn't need to match?  If you make a film of dynamic polymers  which can undergo dynamic component recombination,  you can superimpose these two films.  And let's now look at A and B as two components of the film.  A might be a dye amine.  B might be a bis carbonyl.  So A, B, A, B, they are all together,  forming that dynamic polymeric chain.  You can then make another film which has another dye amine,  A prime, and another bis carbonyl compound, B prime,  and you make then the chain, A prime, B prime,  A prime, B prime.  Now you superpose the two films.  What would happen? What can happen?  This connection is in principle dynamic.  And then, of course, it can disconnect and recombine  with the film below.  In other words, A can now combine with B prime,  and A prime can combine with B. That  means that you can generate inside your material  the two new combinations which did not exist before.  And that can be quite interesting,  because they may have other properties.  They may change the property of the material itself  in a way which is a dynamic way.  Let's assume these are the imines,  but they can be other functions of that type.  And so how can one make use of it?  Several ways have been tried and have been implemented.  One is to change the mechanical properties of the objects.  Another one is to change the hydrophilicity or hydrophobicity.  But the best illustration is by looking at optical properties,  because you see it.  And these optical properties can be changed for such a material  by just recombination of the pieces inside the film.  You can hope for generating changes in color  and in fluorescence of these dynamic polymers.  How?  Again, you have a film AB.  I go back to the same nomenclature.  You have a film A prime B prime.  You superimpose just a part of it, for instance, the corner.  At that place where it's superimposed,  what I just showed on the previous slide can happen.  Recombination of the components so as to generate A, B prime,  and A prime B. A combining with B prime and A prime  combining with B. If one of these two combinations  has a color, it will be generated.  You will see it.  Or if it has a fluorescence, you will see it also.  In other words, you may optically see  whether the recombination, which I'm talking about, has occurred.  Now, this was a collaboration with Mitsui Chemicals.  And they were sending collaborators,  from Japanese collaborators from their plant in Chiba, to my lab.  So we were developing the basic results in that.  And they were interested in potential applications.  So my Japanese coworkers then, they like these nice little pictures.  This is a cat head, where the head and the ears is AB.  Inside of the ears, the eyes and the mustache is A prime B prime.  You superimpose.  And then you just let the reaction go.  You help it by heating.  You get color and you get fluorescence.  Only when it's superimposed.  That shows, of course, that the exchange works.  That there is indeed a recombination at the interface  between the two films.  It also indicates that potentially it  is possible to use, for instance, a heating laser  to write at the interface between two films.  Or if you make a stack of the films,  you might be able to write in three dimensions.  We have not tried that, but I'm sure there  might be bright engineers around the world making  very good films and making very nice ways of handing them,  superimposing them, and trying them out  for this type of purpose.  So making them, therefore, materials  which are responsive to external stimuli.  This can be applied to the basic classes of biopolymers.  We have done it in all three cases,  but it's just scratching the surface for the moment.  One can make dynamic nucleic acids where the components  bearing a nuclear base, which can be connecting together  to make a strand, but can apply to dynamic peptoids.  It's not really peptide because you  need to introduce the reversible function, where,  for instance, here, the hydrosyth of an amino acid  can be combined either with a function contained  on the other side of the amino acid  or with a complementary type of amino acid.  And then you get a peptoid where there are reversible connections  and which then may exchange amino acid-like pieces.  That is also quite interesting because if one  of these combinations, which is formed by exchange,  has a conformation which is particularly stable,  that's the one you should generate.  Finally, you can also do it with sugars, carbohydrates,  and make dynamic like odenomers, like, for instance,  this one, which is an oligoarabino-theranos,  where you have here a reversible combination  and making a dynamic glycodynamic chain.  These three areas are still, I think, of much interest.  Of course, you can think of combining the amino acid subunit  to a sugar subunit to make mixtures between glycosidic  and peptoid type of entities.  And you can also think of course with dynamic nucleic acids.  So I think there's a lot of work to be done there  and maybe also for interesting biological  and maybe even drug applications generating combinations  which might have interesting bindings to membrane surfaces,  to just to trapping molecules and so on.  I can imagine many things, but a lot of work is involved.  And for instance, for denoting peptoids,  Anahirsh is now continuing that work.  Now, what about this adaptive chemistry then?  Adaptive chemistry is to make entities  which can undergo variation in their constitution,  not shape, constitution, depending on some agent,  like the medium, the phase change, physical effector,  can be heat, can be pressure, can be electric field,  chemical effector, and even a change in conformation.  These type of changes are included in a network.  I come back to what I need to a network.  I just mentioned it here.  And make it to adaptive chemical systems.  I would like to illustrate that by the following way.  Suppose you have these two monomers which have a strong,  a big hydrophobic core and a side chain  which makes them water soluble.  This is a di-carbonil.  That's a dihydrozyte.  So if you mix those two, what do you get?  You get the polycondensation.  And we had independently studied that you get a polymer,  which is quite an interesting one, which is characteristic  inasmuch as hydrophobic effects in water  will try to minimize contact between the hydrophobic core  and the aqueous solution, the aqueous phase.  Therefore, putting the core inside a rigid rod  and having the chains which make it soluble in water sticking out.  OK.  In itself, it's an interesting polymer.  But the interesting question you can then ask,  is you now ask the system to solve a question,  to give an answer to a question.  The question is, let's mix these two  where you have a small hydrophobic core  and a large hydrophobic core.  And now ask this other component to choose between the two,  which will be included in the dynamic polymer.  If you work in water, you would expect,  and that goes to have perhaps already guessed,  that you will still get the same.  And this will just stay out because the system,  somewhat dynamically, will push towards excluding  contacts between water and the hydrophobic core.  And indeed, that is what happens.  You have a selective polymerization of this with that,  despite the presence of the other one.  But then you can do a counter experiment  just to show this if this is correct.  If you go progressively from pure water  to organo-water mixtures, you should lose the selectivity.  And indeed, when you add acetonitrile,  you add 80% acetonitrile added.  You have random incorporation.  So you have lost this hydrophobic driving  effects, which make the system select for one component  and excludes the other one.  So you have a component selection,  which is based on exclusion of contacts  between hydrophobic pieces of the molecule and water.  Another case of interest is work done in collaboration  with one of my colleagues, Paolo Samoé.  It was much more had been done there.  But let me just summarize one aspect related  to what I'm telling you.  Suppose you have this long chain  of aldehyde, which deposits very well on a surface.  And you mix it with these three diamines.  You deposit that on a graphite surface,  and you look at the STM pictures of what happens.  If you look first at the solution, the phenyl-octane solution,  what you find in that solution by NMR  is simply mono-E-means, not diamines,  and only 1% to 5% to PC means, and a mixture of all three,  which is what you expect.  Just a statistical mixture, but only a simple single mean.  Now you deposit that on a surface.  What you now have is only one compound and only PC main.  Because that's the one which adsorbs best.  That means adaptation to the surface  pushes the system to generate here  to drive a complete reaction, driving the reaction to completion,  and selecting for the best, most stable PC main.  That means that adaptation occurs to the adsorption  to the surface.  It's adsorption forces, which leads  to the selection of the right components.  And it's a self-organization on the surface, which leads to it.  It's interesting that this is perhaps also  interesting at the origin of life scenarios.  Because if things deposit, if selection  can occur simply by deposition and interactions,  there could be an interesting contribution there  to select D by adsorption forces.  Now let me come to this notion of networks.  This notion of networks is that you  would like to try to see if these entities, they really  talk to each other.  You have a mixture where they exchange components.  So each of them talks to the other one.  Let's look at the simplest case.  If you have, again, I come back to this new microtrax,  A, A prime, and BB prime, which can react with each other  to generate AB, AB prime, A prime, B, A prime, B prime.  These four exchange their pieces.  And therefore, they form a network.  And this simple network is, in this case,  the simplest you can imagine, a square.  You can then put the four constituents  at the corners of the square and look  at their relationships.  On the edges, the constituents have a component in common.  AB has in common A with AB prime and B with A prime B.  So if AB increases for some reason,  it does it at the expense of these two,  which means these are antagonists.  On the other hand, on the diagonals,  the relationship is agonistic.  If AB increases, it liberates A prime and B prime,  which can make more A prime, B prime.  Therefore, you have two types of relationships,  antagonistic on the sides of the square,  and agonistic on the diagonals.  Now, what can I do with this?  Of course, in a very, we have now more complicated networks  with up to nine components.  And this could be an interesting, more complicated  relationship there, but let me look just at the simple one.  Because we can act on one of those thoughts,  did one of those constituents, and see  what how the other ones respond.  And this would then be an adaptive chemical network,  the chemical network, which will respond to agents.  So let's have a look at, first of all, a very simple illustration,  and then a somewhat more complicated one to conclude.  Suppose you have a statistical mixture of these four constituents,  where AB have what I said, A are the altitudes,  B are the hydrosites, and you have these four constituents.  Now, you treat with a metal.  In among those four, there is one we  should bind the metal very well, which  is the one which has NNO3 coordination sites.  If you add some base, it will ionize the NH  and have a more stable complex.  The result is, as you add the metal to this mixture of four,  you get only two at the end, because you strongly amplify AB  by binding of the metal.  But as the consequence, A prime, B prime  will also be amplified.  I come back to that, because I find  that is one of the most important conclusions.  So you have amplification of one constituent  by driving the system with the metal.  Yeah.  So you have these four constituents, and you get this.  And then you amplify, and you get this amplification of AB,  and also of A prime, B prime.  What does that mean?  That means that you have an adaptation  to the addition of the metal.  And that you have what I call an agonist amplification.  In other words, the fittest for binding the metal  amplifies also the unfittest.  Unfittest for that property, but maybe good for something else,  which might indeed be interesting,  because the unfittest may have some other properties.  Let me just conclude rapidly.  In view of time, I will be short.  But just to illustrate an important driving force, which  is self-organization, organization of system, which  leads to a higher organization that is starting material.  It is well known that Guanines form a Guanine G-quartet,  and they form then a gel.  Now a gel is more organized than a solution.  So what can you do with these forces of gelification  of this organization?  You can take a set of components.  One of them be having a guanosine residue,  and the other ones having the connection possibilities,  with this NH2 here, periodoxal or sulfonated  benzaldehyde, and another piece, which  is derived from alanine.  So you mix that, what do you get?  So this is here from Cering.  What you get here is that you get now a gel.  In the solution, which is included in this gel,  in the pieces which are still a solution,  you have three components.  In the gel, you have only one.  The one, of course, is formed as a gel.  But interesting thing is not only that.  That is quite obvious, that the one  is formed as a gel is the one which contains the guanosine,  the guanine residues.  The one is formed as a sol are the others.  But you can see that the proportions are such  that AB is strongly amplified by gel formation.  As a consequence, A by pre-prime  is also strongly amplified.  Again, therefore, you have an amplification  of the constituent, which leads to the organized state.  Whereas the agonist, which is the counterpart, which  is in the solution, is also amplified.  So you have a self-organization.  You have a selection of components,  either self-organization pressure.  To summarize, in the beginning, you  have statistical distribution.  You let gel formation occur.  You have amplification of the one which forms a gel  and the one which does certainly not form a gel,  the least able to form a gel.  This is a self-organization driving force.  And therefore, you can say that self-organization drives  component selection in a way to generate the best  for making an organized state.  And of course, amplifies also its agonist.  This adaptation results in adaptation  under the pressure of self-organization.  Again, stabilizing the fittest here, not by a metal line,  but by self-organization forces also  drives the amplification of the unfittest for that,  the most soluble one.  And this is perhaps also interesting again  for pre-biotic origin of matter.  Because if a system is such that,  it may select for a more organized state,  it will select the pieces it needs  to form the more organized state.  And this before any selection can occur on biological nature,  this is a purely chemical way of proceeding.  So let me just summarize.  As chemists, we have to start with molecules.  On basis of molecular chemistry, we  can then develop a supramolecular chemistry, which  leads to organized entities, which then are dynamic  or can be made dynamic.  For instance, when covalent, you have to make them dynamic,  then they can become adaptive.  And that is now the thing which you are mostly interesting,  making systems which are adaptive,  which respond to different type of forces,  like crystallization, like vaporization,  like inference of metal ions, all like.  And for the most intriguing one is under the pressure  of self-organization to lead to more complex states of matter.  I think in the future, having this evolution of chemistry,  if I could say it's an evolutionary chemistry even,  having forces which lead to more and more complex states  by themselves, selecting the more complex states,  the more organized states, by selecting the right pieces.  I hope that is one of the perspectives for chemistry.  Thank you very much.  Thank you.  Thank you.  Thank you.  Thank you.
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It's nice to be back in Lindow. Now, this is another setting, as the one I had been in last time. And it's quite nice one. I must say I prefer that perhaps to the more modern type of setup. Anyway, so let me tell you about some perspectives in chemistry. And now we are very interested in developing an area which we may call adaptive chemistry. We'll try to explain what it is about. Now, as you know, we have chemists who are supposed to be able to make molecules, to design them by using linking atoms to covalent bonds. Beyond that, there is an area which we have now developed for many years, which is super molecular chemistry, which deals with the way in which molecules interact. And three main functions were studied over the years. How do molecules recognize each other? We have a lot about that, because in biology, any function starts first with a recognition process. Then how do they react with each other? How can they carry each other through a membrane? And recognition is the basis of this. But we think a bit more about what happens beyond super molecular chemistry. What can we learn from it? It is quite obvious, but it was taken for granted for many years, that super molecular chemistry is a dynamic chemistry inasmuch as the pieces linked together by these non-covalent rather labile interactions, these pieces can exchange. And therefore, a super molecular object can undergo variation in constitution by exchanging its components. Now, this then led to the idea that in fact this is a dynamic chemistry which relies on non-covalent labile interactions to exchange the pieces. The next step was to see whether or not one can introduce these dynamic features residing in the constitution of the object to molecular structures. And indeed, this can be done if a molecule is constituted by atoms linked through non-stable bonds, bonds which can break and then exchange also pieces. That was something a bit disturbing, because when you make molecules, you want them to be stable. And if they're not stable, you usually cool them down in a fridge or whatever just to keep them from breaking up. But you can ask the question, let's turn the question around, and say what would happen if we now make molecules which do the reverse, which exchange their pieces? And this then led to the idea that there must be perhaps an interest in studying a dynamic covalent chemistry. You can then combine these two under the same title, the same roof, and calling this a dynamic chemistry residing in the constitution of the chemical object. That chemical object can be molecular or it can be super molecular. So it is a dynamic chemistry based on the constitution of the chemical object. And this opens then the possibility that your entities may be able to adapt, to open the possibility of an adaptive system where the system might respond in its constitution by exchanging its components to stimuli of physical nature or to chemical effectors. And that opens possibly the road to an adaptive chemistry. Now, this constitutional dynamic chemistry, what is it good for? First of all, it makes a mess. It makes a mixture. But you may call now a library, of course a much nicer name, in older times who called that a mess and you throw it away. But now we think that it might be very interesting to study the diversity generated and indeed this generates diversity on both the super molecule and the molecular level and then makes possible something which is also a term which perhaps for biologists is more common, but which is interesting, the fact that you can select pieces, you can select different constitutions of interest for biologically active substances, discovery of biological substances which are active, and implementing dynamics in nanodevices and also perhaps making dynamic materials, like dynamic polymers. I will only discuss two parts of it, the biologically active substances and the dynamic materials. First you have to choose a reversible chemical reaction. There are many. We have mostly studied an emblematic one which is the condensation of a carbonyl with an NH2 giving an emin. That's a nicely reversible reaction. It's not so simple as it looks on the screen, in fact, but it is a nice one which one can study and there are good reasons for that, that both organic molecules bearing it and of course bio molecules. Other reactions can be studied. The group of Jeremy Sanders in Cambridge has studied mostly disulfide formation exchanged by making disulfide bonds and exchanging the pieces. So, immune formation. This is just the framework, just the basic reaction, but I would like to understand the concepts behind. That's just the workhorse, so to say. So, how can you come to searching for biologically active substances by using this kind of principle? If you go back to the image of Emil Fischer of the key and the lock, how can you make a key for biological lock? This would be the key, would be the biologically active substance for binding to the biological target, the lock. So, the design chemistry would be to make one key the right one for the lock. That may be difficult because you have to know the lock. You have a lot about x-ray crystallography and also about dynamics. You have to know the lock, you have to build the key, you have to test it. Another approach is to try a sort of random means of generating a lead substance by making very many keys, just trying them out and hoping that you will find one which may have some interesting activity and then you can improve on it. But this one, of course, is not teaching you much about how molecules recognize each other. So, how can you combine the information which is present in the recognition process, one key for the right one, or the possibility to study many, many molecules, sort of a computer-tool approach? This would be nice if you can do a dynamic combinatorial which relies on the generation of fragments, I come back to that. And this would then combine combinatorics, that means the way in which you can recombine the pieces so as to generate a very high diversity and informatics the way in which these things interact, the information stored in the molecules and which leads to these recognition processes. Just one slide to illustrate that, because I would like to go to other things. If these are the components of different structures, different types of structures, with here a point, this black dot, which is a functional group which can undergo reversible connection. When you mix those together, you generate an interconverting set of constituents. You have access through this reversible reaction to all the possible combinations of the pieces. Now, this gives a complex mixture of entities all the time interconverting. So what can you do then? You lose a basic law of thermodynamics, which is that you add the receptor and the receptor should best bind the combination which is the most suitable for this receptor site. And that means that the lock and key will be sort of a dynamic key which the lock will then select and lead to the most stable binder. In other words, the lock does the driving, the lock assembles its own key. In fact, this can be used then for trying to track discovery processes. It has been used and applied for discovering enzyme inhibitors and also for looking at substrates for biological artificial or biological receptors. I don't want to go more into that, but the principle has been demonstrated in a number of cases. Now, I would like to switch to what you can do in the field of materials. Dynamic materials look like something also one of sort of a thing which you might not like to do because you don't want to make really materials which fall apart. But they maybe have properties, perhaps, which are different from static materials because they might be self-healing, responsive, adaptive materials. Let's look at a class of materials, dynamic polymers, which we like to call dynamers. These dynamic polymers can be of two types. One type is on the molecular level, if this is a monomer with two functional groups at each end of a given spacer. And this is another monomer with two functions at the end of a spacer. And if these two functional groups are complementary, complementary meaning that they can undergo a reversible reaction, then you get a chain which is dynamic in its constitution because these connections can break reversibly and that would then be a molecular dynamic polymer. On the other hand, if it is not a polygondensation but a polyassociation through interactions, then these entities, the red one, are interaction complementary interactional groups undergoing molecular recognition. And then it's a super molecular non-covalent dynamic polymer. Let's have a quick look at the super molecular polymer chemistry. This is a field which developed quite a bit over the last 30 years or so and it was a bit difficult to have it to convince polymer chemists at the beginning but now it's well accepted and that will just illustrate a point. What can one do on the basis of the super molecular polymer chemistry? How does it build up? I mentioned here the date when we published the principle, the first time we published that where the principle was introduced in 1990 because I need this date 1990 in a moment, as you will see. So the principle is simple. I just quickly mention it. You have a spacer, you have two end groups. These end groups here are hydrogen bonding groups undergoing donor, acceptor donor of hydrogen bond formation and the complementary to DAD is then ADA, acceptor donor acceptor, so that if you mix this component with this component, the result is the formation of a super molecular polymer main chain where the polymeric entity is linked, where the units are linked together by forming three hydrogen bonds between the components. Just to illustrate that there is a big difference in material properties, these two are solids and that's a liquid crystal. I don't want to go into more details, but this was just an illustration of the principle of making super molecular main chain polymers, which then was developed a lot, especially by Bert Meyer in Eitoven, where a lot of very nice work was done to develop the ideas and to make a range of compounds and materials also by a number of other groups. This is an electron microscopy picture showing that indeed the material has fibers which can connect together, I don't want to go more into the details. Why do I mention that? First of all, because it is a dynamic polymer, it is a polymer based on non-covalent interactions, but also to illustrate how long it can take to go from basic concept to an application. In 2003, one can look at the possibility to have self-healing materials. Let's have a look here. That's a transparent film which contains entities which are linked by non-covalent interactions. You can cut this film in two, superimpose the two ends, and then you press with your finger just for some time, not very quantitative, but you press with your finger and you can stretch and it sticks again. I have a movie for that, but I didn't want to show it, it takes a bit too much time just to get from one thing to the other one. But you can see this, you can stretch, and it has the mechanical properties almost the same as the starting film. This, the reason that it is not the same is probably that it was not pressed long enough and there was not a very quantitative way of doing things, but this just demonstrates that supermolecular polymer films are self-healing materials. Now, the other point of importance is in addition to having this practical material type of application, there is another possibility, and in 2013, in October of that year, I got an email from a small company saying, we have developed supermolecular polymer materials which are biocompatible. And what they had done is using supermolecular materials, this company Xeltis, has used this type of material to make cardiovascular implants. These cardiovascular implants were then used for the reconstruction of the heart of children who had a congenital cardiac malformation. It was indeed done, and here you see the first young girl who was implanted by Leo Boqueria, he's a cardiovascular surgeon at the Bakulev Scientific Center for Cardiovascular Research in Moscow. This was in 2013, it's now almost four years later, and she's fine. Many more children have now been implanted, at least 10, but I haven't followed all of it, so more than that. So that is, of course, for when you do basic research, it's great satisfaction to see that some of the principles introduced many years earlier, finally, came to a material which is now present and used in surgery for children. This has now been developed also by the same company to make a heart valve, which is shown here, which was implanted in July 2016, and which, for the moment, is also going well. They tell me that it's really a big change in surgical practice. Now, this is just about supermedical polymers, and as I said, this field has now developed very much, and there's a lot of work going on in the area. What about now making dynamic polymers which are covalent, where the connections between the pieces are covalently reversible? Then you would simply think of doing something which any chemist is sort of a very simple kind of thing to do, is to dye carbonyl, the dye amine, you mix them together, and you get a polyemine. No big deal, and you can make them for polyemines, or you can use hydrazine to make polyazole hydrazones. This is just something which, for a chemist, is quite a normal thing to do. So now, what can one do with this type of polymers? What can one use them for? Are they interesting, or are they just some kind of idea which doesn't need to match? If you make a film of dynamic polymers which can undergo dynamic component recombination, you can superimpose these two films. And let's now look at A and B as two components of the film. A might be a dye amine. B might be a bis carbonyl. So A, B, A, B, they are all together, forming that dynamic polymeric chain. You can then make another film which has another dye amine, A prime, and another bis carbonyl compound, B prime, and you make then the chain, A prime, B prime, A prime, B prime. Now you superpose the two films. What would happen? What can happen? This connection is in principle dynamic. And then, of course, it can disconnect and recombine with the film below. In other words, A can now combine with B prime, and A prime can combine with B. That means that you can generate inside your material the two new combinations which did not exist before. And that can be quite interesting, because they may have other properties. They may change the property of the material itself in a way which is a dynamic way. Let's assume these are the imines, but they can be other functions of that type. And so how can one make use of it? Several ways have been tried and have been implemented. One is to change the mechanical properties of the objects. Another one is to change the hydrophilicity or hydrophobicity. But the best illustration is by looking at optical properties, because you see it. And these optical properties can be changed for such a material by just recombination of the pieces inside the film. You can hope for generating changes in color and in fluorescence of these dynamic polymers. How? Again, you have a film AB. I go back to the same nomenclature. You have a film A prime B prime. You superimpose just a part of it, for instance, the corner. At that place where it's superimposed, what I just showed on the previous slide can happen. Recombination of the components so as to generate A, B prime, and A prime B. A combining with B prime and A prime combining with B. If one of these two combinations has a color, it will be generated. You will see it. Or if it has a fluorescence, you will see it also. In other words, you may optically see whether the recombination, which I'm talking about, has occurred. Now, this was a collaboration with Mitsui Chemicals. And they were sending collaborators, from Japanese collaborators from their plant in Chiba, to my lab. So we were developing the basic results in that. And they were interested in potential applications. So my Japanese coworkers then, they like these nice little pictures. This is a cat head, where the head and the ears is AB. Inside of the ears, the eyes and the mustache is A prime B prime. You superimpose. And then you just let the reaction go. You help it by heating. You get color and you get fluorescence. Only when it's superimposed. That shows, of course, that the exchange works. That there is indeed a recombination at the interface between the two films. It also indicates that potentially it is possible to use, for instance, a heating laser to write at the interface between two films. Or if you make a stack of the films, you might be able to write in three dimensions. We have not tried that, but I'm sure there might be bright engineers around the world making very good films and making very nice ways of handing them, superimposing them, and trying them out for this type of purpose. So making them, therefore, materials which are responsive to external stimuli. This can be applied to the basic classes of biopolymers. We have done it in all three cases, but it's just scratching the surface for the moment. One can make dynamic nucleic acids where the components bearing a nuclear base, which can be connecting together to make a strand, but can apply to dynamic peptoids. It's not really peptide because you need to introduce the reversible function, where, for instance, here, the hydrosyth of an amino acid can be combined either with a function contained on the other side of the amino acid or with a complementary type of amino acid. And then you get a peptoid where there are reversible connections and which then may exchange amino acid-like pieces. That is also quite interesting because if one of these combinations, which is formed by exchange, has a conformation which is particularly stable, that's the one you should generate. Finally, you can also do it with sugars, carbohydrates, and make dynamic like odenomers, like, for instance, this one, which is an oligoarabino-theranos, where you have here a reversible combination and making a dynamic glycodynamic chain. These three areas are still, I think, of much interest. Of course, you can think of combining the amino acid subunit to a sugar subunit to make mixtures between glycosidic and peptoid type of entities. And you can also think of course with dynamic nucleic acids. So I think there's a lot of work to be done there and maybe also for interesting biological and maybe even drug applications generating combinations which might have interesting bindings to membrane surfaces, to just to trapping molecules and so on. I can imagine many things, but a lot of work is involved. And for instance, for denoting peptoids, Anahirsh is now continuing that work. Now, what about this adaptive chemistry then? Adaptive chemistry is to make entities which can undergo variation in their constitution, not shape, constitution, depending on some agent, like the medium, the phase change, physical effector, can be heat, can be pressure, can be electric field, chemical effector, and even a change in conformation. These type of changes are included in a network. I come back to what I need to a network. I just mentioned it here. And make it to adaptive chemical systems. I would like to illustrate that by the following way. Suppose you have these two monomers which have a strong, a big hydrophobic core and a side chain which makes them water soluble. This is a di-carbonil. That's a dihydrozyte. So if you mix those two, what do you get? You get the polycondensation. And we had independently studied that you get a polymer, which is quite an interesting one, which is characteristic inasmuch as hydrophobic effects in water will try to minimize contact between the hydrophobic core and the aqueous solution, the aqueous phase. Therefore, putting the core inside a rigid rod and having the chains which make it soluble in water sticking out. OK. In itself, it's an interesting polymer. But the interesting question you can then ask, is you now ask the system to solve a question, to give an answer to a question. The question is, let's mix these two where you have a small hydrophobic core and a large hydrophobic core. And now ask this other component to choose between the two, which will be included in the dynamic polymer. If you work in water, you would expect, and that goes to have perhaps already guessed, that you will still get the same. And this will just stay out because the system, somewhat dynamically, will push towards excluding contacts between water and the hydrophobic core. And indeed, that is what happens. You have a selective polymerization of this with that, despite the presence of the other one. But then you can do a counter experiment just to show this if this is correct. If you go progressively from pure water to organo-water mixtures, you should lose the selectivity. And indeed, when you add acetonitrile, you add 80% acetonitrile added. You have random incorporation. So you have lost this hydrophobic driving effects, which make the system select for one component and excludes the other one. So you have a component selection, which is based on exclusion of contacts between hydrophobic pieces of the molecule and water. Another case of interest is work done in collaboration with one of my colleagues, Paolo Samoé. It was much more had been done there. But let me just summarize one aspect related to what I'm telling you. Suppose you have this long chain of aldehyde, which deposits very well on a surface. And you mix it with these three diamines. You deposit that on a graphite surface, and you look at the STM pictures of what happens. If you look first at the solution, the phenyl-octane solution, what you find in that solution by NMR is simply mono-E-means, not diamines, and only 1% to 5% to PC means, and a mixture of all three, which is what you expect. Just a statistical mixture, but only a simple single mean. Now you deposit that on a surface. What you now have is only one compound and only PC main. Because that's the one which adsorbs best. That means adaptation to the surface pushes the system to generate here to drive a complete reaction, driving the reaction to completion, and selecting for the best, most stable PC main. That means that adaptation occurs to the adsorption to the surface. It's adsorption forces, which leads to the selection of the right components. And it's a self-organization on the surface, which leads to it. It's interesting that this is perhaps also interesting at the origin of life scenarios. Because if things deposit, if selection can occur simply by deposition and interactions, there could be an interesting contribution there to select D by adsorption forces. Now let me come to this notion of networks. This notion of networks is that you would like to try to see if these entities, they really talk to each other. You have a mixture where they exchange components. So each of them talks to the other one. Let's look at the simplest case. If you have, again, I come back to this new microtrax, A, A prime, and BB prime, which can react with each other to generate AB, AB prime, A prime, B, A prime, B prime. These four exchange their pieces. And therefore, they form a network. And this simple network is, in this case, the simplest you can imagine, a square. You can then put the four constituents at the corners of the square and look at their relationships. On the edges, the constituents have a component in common. AB has in common A with AB prime and B with A prime B. So if AB increases for some reason, it does it at the expense of these two, which means these are antagonists. On the other hand, on the diagonals, the relationship is agonistic. If AB increases, it liberates A prime and B prime, which can make more A prime, B prime. Therefore, you have two types of relationships, antagonistic on the sides of the square, and agonistic on the diagonals. Now, what can I do with this? Of course, in a very, we have now more complicated networks with up to nine components. And this could be an interesting, more complicated relationship there, but let me look just at the simple one. Because we can act on one of those thoughts, did one of those constituents, and see what how the other ones respond. And this would then be an adaptive chemical network, the chemical network, which will respond to agents. So let's have a look at, first of all, a very simple illustration, and then a somewhat more complicated one to conclude. Suppose you have a statistical mixture of these four constituents, where AB have what I said, A are the altitudes, B are the hydrosites, and you have these four constituents. Now, you treat with a metal. In among those four, there is one we should bind the metal very well, which is the one which has NNO3 coordination sites. If you add some base, it will ionize the NH and have a more stable complex. The result is, as you add the metal to this mixture of four, you get only two at the end, because you strongly amplify AB by binding of the metal. But as the consequence, A prime, B prime will also be amplified. I come back to that, because I find that is one of the most important conclusions. So you have amplification of one constituent by driving the system with the metal. Yeah. So you have these four constituents, and you get this. And then you amplify, and you get this amplification of AB, and also of A prime, B prime. What does that mean? That means that you have an adaptation to the addition of the metal. And that you have what I call an agonist amplification. In other words, the fittest for binding the metal amplifies also the unfittest. Unfittest for that property, but maybe good for something else, which might indeed be interesting, because the unfittest may have some other properties. Let me just conclude rapidly. In view of time, I will be short. But just to illustrate an important driving force, which is self-organization, organization of system, which leads to a higher organization that is starting material. It is well known that Guanines form a Guanine G-quartet, and they form then a gel. Now a gel is more organized than a solution. So what can you do with these forces of gelification of this organization? You can take a set of components. One of them be having a guanosine residue, and the other ones having the connection possibilities, with this NH2 here, periodoxal or sulfonated benzaldehyde, and another piece, which is derived from alanine. So you mix that, what do you get? So this is here from Cering. What you get here is that you get now a gel. In the solution, which is included in this gel, in the pieces which are still a solution, you have three components. In the gel, you have only one. The one, of course, is formed as a gel. But interesting thing is not only that. That is quite obvious, that the one is formed as a gel is the one which contains the guanosine, the guanine residues. The one is formed as a sol are the others. But you can see that the proportions are such that AB is strongly amplified by gel formation. As a consequence, A by pre-prime is also strongly amplified. Again, therefore, you have an amplification of the constituent, which leads to the organized state. Whereas the agonist, which is the counterpart, which is in the solution, is also amplified. So you have a self-organization. You have a selection of components, either self-organization pressure. To summarize, in the beginning, you have statistical distribution. You let gel formation occur. You have amplification of the one which forms a gel and the one which does certainly not form a gel, the least able to form a gel. This is a self-organization driving force. And therefore, you can say that self-organization drives component selection in a way to generate the best for making an organized state. And of course, amplifies also its agonist. This adaptation results in adaptation under the pressure of self-organization. Again, stabilizing the fittest here, not by a metal line, but by self-organization forces also drives the amplification of the unfittest for that, the most soluble one. And this is perhaps also interesting again for pre-biotic origin of matter. Because if a system is such that, it may select for a more organized state, it will select the pieces it needs to form the more organized state. And this before any selection can occur on biological nature, this is a purely chemical way of proceeding. So let me just summarize. As chemists, we have to start with molecules. On basis of molecular chemistry, we can then develop a supramolecular chemistry, which leads to organized entities, which then are dynamic or can be made dynamic. For instance, when covalent, you have to make them dynamic, then they can become adaptive. And that is now the thing which you are mostly interesting, making systems which are adaptive, which respond to different type of forces, like crystallization, like vaporization, like inference of metal ions, all like. And for the most intriguing one is under the pressure of self-organization to lead to more complex states of matter. I think in the future, having this evolution of chemistry, if I could say it's an evolutionary chemistry even, having forces which lead to more and more complex states by themselves, selecting the more complex states, the more organized states, by selecting the right pieces. I hope that is one of the perspectives for chemistry. Thank you very much. Thank you. Thank you. Thank you. Thank you.
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