 OK, zelo se zelo svoj všeč. In v tem, da je prist, vzelo se v svoj moroči, nekaj, da je tudi počke, da se je 45 minuta vzelo za vsega, plus 5 minuta za vsega, in potem sem sem zelo tudi, da sem se zelo, da sem se zelo, 5, 2, 0. Zelo, in potem, da je polizman, ki so vsega, ki so vsega, ki so vsega. OK, So let's start with David Lay from the University of Manchester and I think that he is going to talk about not synthetic chemistry. Thanks very much and first of all a big thanks to Christian and the other organisers for giving me the chance to come here and tell you about the sort of things that we're doing over in rainy Manchester. And I'd like to congratulate them on their bravery for having a synthetic chemist who was the first talk of the meeting. I promise to be gentle and not to really go into any detail about the methods of what we do, but I just want to give you a general impression about how we do what we do. And most importantly the most of the sorts of things that we can make and hopefully to interest people and challenge people into thinking how they might want to incorporate the sorts of things that we do into their own work and their own systems. Ok, so I'm a synthetic chemist and the sort of molecules that we make are ones which are held together, where the components are held together by mechanical bonds and this is one example. It's called a catenane to chemists or a molecular link to give it its topologically correct name and you can see that the components are linked together and can't be pulled apart without breaking a bond. There's another sort of mechanically interlocked architecture that some chemists like us are interested in and this is where a ring is locked onto a chain and held in, it can't fall off because of these bulky and these molecules are called rotaxanes from the Latin rota meaning wheel and axis meaning axis and the reason that chemists are interested in these mechanically interlocked structures is because of the possibility of using that mechanical linkage of the components not being able to fall apart to allow large amplitude motions between the components and perhaps using those as the basis of molecular machines. So this is an example of a link, a catenane where the ring is driven directionally this small blue ring around the larger ring by use of a chemical fuel in exactly the same way as ATPAs directionally rotates the components in biology. This is a rotaxane, so this one's a catenane, a link, this one's a rotaxane and this is a very crude synthetic analogue of the ribosome in the cells which builds up the proteins in your body and it works by having mechanical threading of this chain through this ring and then this ring is able to move down the track this one here, pick off these building blocks using catalytic methods and build a new chain on the new growing polymer chain on a new part with sequence information and so rotaxanes they're both of these sorts of molecules links and rotaxanes are mechanically linked but these are obviously topologically trivial because if you just expanded the ring you could bring it out over the stoppers and of course because chemical bonds have a finite length you can't do that in practice and so these are mechanically locked even though they're topologically trivial and of course links like knots are topologically complex even if you were able to deform them you wouldn't be able to take the components apart and just as knots are found in biology so are links this is an example of a capsid with proteins that are held together like chain mail on the surface and even rotaxanes are found in biology this is Microsyn J25 which is a very small lasu peptide where this ring can't get off this chain because of these two bulky amino acids either side that hold this ring in place but how do we make these sorts of threaded structures so that it's hard enough to think how to thread the eye of a needle in the big world how are we going to thread the eye of a needle when that needle eye is only one nanometer apart and the answer that synthetic chemists use is to use this concept of self assembly and I was trying to figure out how to illustrate that to you all today but when I got up today in fact I went in the guest house I don't know if you saw that dog lying around but I got to my newspaper before me which of course ruined the newspaper but it did get me thinking that of course a newspaper is a very complicated information rich structure which requires lots of effort by lots of different people to put together every day you need obviously the writers to write these sorts of stories that we're going to need we need the editors to always need editors to edit the sort of things that we write make sure it's the right length and that it's all fits together you need the copy setters to set the stories and link them together so they fit on the page you need the printers to actually print the newspaper you need to send it out to our shops and actually get the newspaper over to us so it's a very complicated involved process which requires lots of people to work on and I was wondering wouldn't it be much simpler if there was a better way of taking the building blocks and getting them to sort of self assemble and produce the kind of no, no, no, no, no, no and get them to produce the sort of complex systems that we want and that's what we try and do in our lab try and get simple building blocks build them together and use them to make the kind of architectures that we want and in fact chemists have been doing this for some time and back in the 90s in the middle of the 1980s Jean-Pierre Sauvage had the idea of linking together building blocks to form mechanically complex architectures this is a ligand that binds to copper one-ions which have a tetrahedral geometry that causes these to be orthogonal to each other and if you connect the ends of these together you form a catenane, a link, a molecular link and one of our roles in this or achievements is to, instead of just using the metal to hold the bits in place we've also used the metal as a catalyst to connect the bits together so if you take a ring put a metal in the centre it can bind components either side and then not only hold them in the right geometry to assemble through the centre here but also catalyze the bond forming reaction to give the interlocked product in this case a rotaxane and an advantage of this is that the metal can be recycled and you can do this catalytically with only a small amount of the metal to form the interlocked products so we've developed that in our group and then a few years ago, five years ago now we used this approach which is called active metal template to assemble a molecular knot, a trafo knot and what happens here is we have a ligand strand which is designed so that it binds two copper ions the first copper ion binds these two residues and creates this sort of loop and then this loop has a nitrogen atom in it which can bind a second copper atom in the centre here and that copper atom also binds these two end groups round here and actually catalyzes a bond forming reaction between them so that they're joined together through the loop to form a trafo knot and that was our first foray into getting interested into molecular knots but of course, I'm only going to go over this very quickly but of course as everyone here knows knots have been made since even before humans were present on this planet and the interesting thing from our point of view as people who make stuff is that different functions use different sorts of knots in the big world we have one sort of interlocking or entanglement to produce woven fragments our shoelaces are a different sort of knot fishing lines are a different one and so on and if this is true that different knots have different properties in the big world then presumably it's also going to be true in the very small world we're going to hear much more about these today and of course knots are found in biology and polymers so again, I'm not going to talk about those things but I just want to note that chemistry is actually a very long association with topology and again, this audience will be very familiar that topology started with Peter Guthrie Tate actually starting to tabulate all of the different sorts of knots that were possible to try and prove Kelvin's suggestion that atoms were different kinds of knots in the ether which didn't turn out to be so true but it had a happy result and this is one of Tate's early knot tables the first seven orders of knot in us but really the astonishing thing from our point of view is that this, as a synthetic chemist is that this table was produced in the 1880s and since then mathematicians have come up with or tabulated more than 6 billion different sorts of knots and until we started our work a few years ago only two, the topologically trivial unknot so just a loop and the trefo knot had ever been made by small molecule chemical synthesis so what we've engaged in a little bit of molecular knot Pokemon got to catch them all and I'll tell you a few of the ones that we've made so far so Savash was, after coming up with his route to a catenane he realized that if he extended this idea of entwining ligonstrands around metal atoms he could make more complicated topology so if we have two of these metals and modify the ligonstrands you can actually make the three crossings necessary for a trefo knot and if you put three metals you can connect the ends together to form a Solomon knot but more correctly called a link because it's a catenane so it's a two link with four crossings in it but if you try and take this idea of making linear twisted systems any further they don't work so you can't make higher order topologies this way because there's just too much distance between these end groups and you get crossings which aren't desired and polymerizations and so on and so a few years ago we wondered whether it was possible to go away from this idea of using linear these are called helikets so linear helikets heliket is just the twisting of ligonstrands around metal ions to form a helix a double helix in this case so instead of using linear helikets where you have this problem of large distances between the end groups could we use cyclic structures which would bring the end groups much closer together and if we joined those together we should be able to get these higher topologies and there was some precedence in these sorts of cyclic structures the Nobel Laureate Jean-Marie Lane in the mid-1990s had shown that you could form these sorts of cyclic double helikets using metal non-metal anions to template the different sizes of rings so you could get a cyclic pentamer in the presence of chloride ions and if you use sulfate then you get a cyclic hexamer so Lane didn't do anything with these he just showed that they were formed but if you connect the ends of these together you should be able to form knots and links it's technically difficult to do this because these end groups actually point away from each other it's not easy to see from this and so there's a lot of entropic problems in trying to design systems that will close the ends and also because you've got multiple connections that need to be made you need to have a way of correcting errors if the molecules connect together in the wrong way if you don't have an error checking step then you'll lose and it'll be a very inefficient reaction and you'll get a lot of byproducts so you need to have what are called reversible chemical reactions which can reform if they form the initial wrong wrong sort of connection and so we modified basically we modified Lane's system in order to be able to do this by getting rid of some of the pyridine groups and replacing them with imine bond formation which is the reaction of this carbon double bond oxygen group with an amine and that's a reversible reaction so it allows us to get the reversibility into it and that allowed us to take these two simple components some iron chloride to heat those up then you do indeed form a pentafol a molecular pentafol or not and it takes some time so obviously this is a complex structure so you mix the building blocks together individually and they will react but not initially to form the product that you want they'll form polymers and oligomers and so polymers have a long relaxation time in NMR spectroscopy and so you see very broad signals but then initially because a polymeric species are present but then if you leave the reaction longer and longer and longer you see the sharpening of peaks which correspond to a single species and once one isolates it turns out to be overwhelmingly this pentafol not and this is the X-ray crystal structure so all these atoms are correctly in these positions in the solid state crystal as proven by X-ray diffraction and this is a 160 atom continuous loop so if we start here in the middle of this blue region you go over, round this metal ion under then over, round this metal ion under, over round this metal ion and under, over and back to we started and you can see that there's this chloride ion in the middle which templates the assembly of the whole structure so you can see as it rotates you can see perhaps this double helical structure of the knot as it passes by the chloride ion you have the helical structure of it going twice round those units so this knot has some interesting properties in its own right you'll recall that it was templated by a chloride ion, that's because these hydrogen atoms that point into the center of the cavity have all their electron density pulled away from them by the ion ions that the pyridine units are connected to so the center of this cavity of the knot cavity is extremely electron poor and it's exactly the right size to fit into the center of it a chloride ion which is why chloride templates this assembly and in fact the resulting knot is an extremely strong binder of chloride ions in fact it's the strongest noncovalent binder of chloride ions that's known and it binds chloride so strongly that you have to keep it in the presence of silver salts which bind to the knot otherwise it will rip chloride ions from the environment from solvent, from glassware from any traces so this is an interesting property of a knotted structure so we were interested in this idea of using circular helicates to make other kinds of knots and a trefo knot should be able to be made from a circular triple helicate by holding the ligand strands in these sorts of positions and then just closing the ends together and we've done that as well using metal ions to template this assembly processes lanthanum ions from the lanthanide series and these sorts of metals are able to coordinate to this kind of ligand strand hold three of them in a circular helicate arrangement around the metal ion and then if we just do a reaction which closes brings these two groups together and closes them together to form a chemical bond then we can form a trefo knot in a very efficient way with these sorts of species this is the crystal structure of a derivative of that molecule so again this is showing the precise position of the atoms in the solid state and you can see the lanthanide in the middle held together by these anions and you can see aromatic stacking interactions and other sorts of things which stabilize these units so the sharp ion among you will see that this actually isn't the same ligand which is attached at one position of the ligand and those enable you to introduce chirality into the structure and this chirality can be used to actually form trefo knots of just one handedness so this chirality controls the self assembly of the helicate around the lanthanide ion so that you only form one of them depending upon which in antipy you start with here and so then if you close the ends you can either form the left handed trefo knot or the right handed trefo knot from these kinds of ligands that's interesting that didn't come up ok so in addition to the using the imine chemistry that we saw before we saw the size of the circular helicates that we use and if we instead of making a pentameric circular helicate we use a ligand strand that forms a tetrameric one slightly smaller then by joining the ends together then we get four crossing units but it's not a knot it's a link so this is actually a Solomon knot or more correctly a link so this is two 64 membered rings which have four crossings so they're more complicated than a normal simple catenane link and again this is made in one step from four ligands, four amyzen in this case four ion atoms so that's five and three and four so a six link would correspond to, if you had two rings in connected that would correspond to the star of David topology and that sort of system could be made but not using the imine chemistry that we developed earlier because if we try to do the imine chemistry it didn't form, we weren't able to form cyclic hexamers, we need a cyclic hexamer to use that so we modified the ligand again to have another pyridine group here and to use come-come double bonds this particular ligand again doesn't work, it does form cyclic hexamer now but the arms aren't pointing in the right directions to favor ring closure so we had to design a new kind of ligand where the steric interactions are here favor twisting of the arms which direct them for ring closure and if you take this sort of ligand and you treat it with iron sulfate which drives hexameric cyclic formation then you form this sort of species this is just showing the mass spectrum of this species to show that it's genuinely there, that's one of the techniques that we use and these groups are now pointing together and if we do have an action which will join these two come-come double bonds then we can even though there's six of these need to be joined in one step that proceeds in more than 90% yield to form the closed star of David catenate and again this is the X-ray crystal structure so the unambiguous assignment of the structure by X-ray crystallography this features 240 membered rings that have just been made in two steps in about 70% overall yield and it's got six crossings and this is again a movie where you can see the cyclic double helix all the way around of the two rings, one ring shown in blue and one ring shown in purple so this knot table that I showed earlier was one of the earliest ones from Tate but it's not actually complete, it's got some missing from it and that's because the early topologists thought that all knots could be written with alternating crossings but that's of course not true and a few years later little showed that there were other kinds of knots non-alternating knots and he modified Tate's tables to include other kind of knots with non-alternating linkages and he put in lots of knots but these were in fact these are all exactly the same and this corresponds to the 819 knot in modern knot tables and the 819 knot is a a torus knot so you can wrap it around a torus it's chiral and it's one of the simplest non-alternating knots together with the two other eight crossings knots so this is its most symmetrical form this is how it appears in most knot tables and sometimes you'll see it written like this which leads to it being called the true lovers knot you can see it in various places such as some islamic art and also I'm sure you're all aware that it's on the symbol of boysy uncles the thrash metal band so it's clearly important to try and be able to make this sort of link and in fact Christian and colleagues in the audience had shown that this was actually a preferred structure in computer simulations if you take helical fragments and allow them to self-assemble of the knots you get the 819 knot is one of these so it has this sort of preferred structure for us and I saw that there was a similarity between the Solomon link kind of topology that we'd made earlier from a cyclic tetraba and an 819 if you superimpose one on the other you'll see that the only difference is actually how you connect these end groups if you open the Solomon link and connect it round here and with the same at each of those you would convert the 819 into the Solomon link and normally in all the systems we've shown before we're using multiple metals to form normally an equal number of crossings so how can we use four metals to make eight crossings well the answer is that the iron atom here is octahedral so it combined to three of these bydentate ligands around it and at the moment two of those are forming the same strand but if we design the ligand strand differently we can actually have that the iron here can hold in relative positions three ligand strands and that's what you need in order to be able to braid strands and make more complicated systems so if you take this modified ligand strand which is expanded so it can't do the kind of folding that we saw that leads to the Solomon link and treat that with iron chloride this is the sort of ligand strand that will form a cyclic tetramer so we get this sort of species again confirmed by mass spectrometry and then if we try and join the ends together we can do that to form a fully unsaturated species closed species in 62% yield this is it by mass spectrometry showing that they should have been formed the proton LMR spectra is really symmetrical which again suggests that it's got this cyclic structure the terminal group protons here have disappeared so we know we've got all ring closures and this is the X-ray crystal structure of that molecule so this is 92 atom continuous loop with 8 non-alternating crossing point so if we start here and we go around we go under under around here over over then under under around here over over under under over I must have gone over over under under right back over over to the start and it's just made in two steps in 61% overall yield from a total of four ligand strands that form a triple helicate now all the way around and if we look at the rotating structure you can see that now it's a triple helicate going around the iron centers in order to braid them into this knot structure so these knots are all the metal out of because the imine bonds aren't stable without the metal ions but these ones the 890 knot now that we've closed it with these extra pyridine groups so we don't have imines anymore we can demetalate these structures and form the completely demetalated knot and you can see that the proton NMR spectra here is quite broad and this is a sign that there's reptation of these chains through the knot that you're getting slow motion of these chains as they process around the knot like reptation in the slokish movement of polymer chains so this is the tightest knotted physical structure that's known it's just 24 atoms per crossing point in the 192 atom chain and it's chiral it's got no euclidean chiral elements so no chiral centers, no chiral helix no axis of chirality nothing but because it's a 890 knot it's chiral and you can separate the knot into the two enantiomers topological enantiomers by chiral HPLC and you can do circular dichroism measurements on these structures so this is the one of the knots, we don't know which enantiomera is and this is the other knot with equal and opposite circular dichroism so circular dichroism shows it's the reflection of the aromatic rings these are aromatic ring regions of the handedness of the environment in those sorts of systems we can also do other alternative connections, especially that one is made by an alternative connection of the Solomon link, the cyclic tetramer structure but if we try doing that on the other circular helikets we've got we can generate other structures so if we connect the N groups together here the closest connections we get the star of David Catternain but if we connected these with at every other connection in this would lead to 9 crossings and it would be a composite knot 3 trefo knots of the same handedness connected together to form this sort of structure and if we take this lig and strand which is not able to form the closest crossings and we treat it with iron 2, with a slightly different counter iron this time we get a cyclic hexamer and if we connect the N groups together by olefin metathesis we get this species and this is the X-ray crystal structure of the first composite knot this 9 crossing composite knot as you can see from the cartoon these strands go back and it's quite hard to go through to do all this over under things so I just have to take my word for it that this is a 324 atom loop with 9 alternating crossings and it's made in 2 steps in 65% overall yield from the root that I mentioned we can also do this same trick of being able to demetalate the systems with the pentafone knot by modifying instead of making the pentafone knot with imines making it with this olecarbon skeleton so if we take this ligand strand put chloride in the centre of it which templates it for a 5-membered circular pentamer close the N groups together we can get this sort of pentafone knot which we can now demetalate this is the X-ray crystal structure again very similar to the previous pentafone knot and if we demetalate it now then we can get the metal free so the pentafone knot and again this is chiral it has no chiral centres no chiral axes no chiral helix nothing, it's just chiral by virtue of its topology you can separate it into the two enantiomers and again this is the circular dichroism spectra of the two knot enantiomers and we can take this free ligand and put different metals into it to form slightly different tighter and not so tight knots you can't do it directly with these metal ions to do with their coordination dynamics but if you put in a zinc which has very fast coordination dynamics you can form this sort of structure and then you can replace the zinc ions one by one and actually make a whole series with different coloured metal ions in iron, cobalt, nickel, copper zinc all in the centre and these have different kinds of properties the centre here is as different sizes now the cavity has different electron density at the centre so it binds anions with different stabilities and we can use these sorts of this is just a comparison of the same method and the other method that we developed so this works is just one step synthesis but it only works well on just a few milligrams a scale and of course as I mentioned you can't pull the metals out of this system otherwise it will just fall apart so it's receiving you can't separate it into two different sorts of knots but this system here you can make grams of it we can pull the metals out and it's completely stable you can resolve it into its enantimus and you can put different metals back in which have different properties and we can use the fact that this topology limits the sort of structures that can be formed by these ligands to do catalysis so if you just take this knotted ligand with no metals in the catalyst for this chemical reaction but if we bind zinc ions to it and we use BF4 then this cavity is empty, BF4 can't get inside of it but if you remember this cavity binds halide ions like bromide and chloride extremely strongly so it will strip the bromide off here once these metals are in and catalyze this chemical reaction and the knot on its own and you can't do it because this cavity won't bind anions unless the metals are present to suck all the electron density out of the cavity so this is allosteric catalysis it requires the binding of these 5 metal ions in order to do the catalysis at a different centre here the anion binding centre and you can go round in this sort of sequence and you can use this to also catalyze other kinds of chemical reactions use this species bromide ions off other carbocations and this species can then catalyze other chemical reactions in its own right so this is initiating catalysis through an anosteric binding mechanism with a knot and the knot architecture is crucial here if you just take ligand strands which are identical but aren't joined together to form the knot they can't do this because when you add the zinc they won't form this knotted structure and even if you do it with iron it will not be chloride in the centre here and so it won't do the catalysis then it's only possible because of this knotted ligand strand I think you've had enough of synthetic chemistry these are all the knots that I've talked about today when we started this work chemists had only in the previous 15 years they'd only made different one sort of knot, savagis, trefo knot and other groups that made trefo knots as well and in the last few years that number of pokemon knots has been increased a little bit I didn't talk about this one today and there's a couple of others that we're working on that we have knots that again I didn't mention why is this possible now well the advances in synthetic chemistry now make these sorts of these sort of structures realistic targets for synthetic chemistry it really wasn't possible to make these sorts of things 10 years ago the synthetic methods that chemists developed just weren't up to weren't up to it and frankly this embarrassing position that chemists have been in that there are 6 billion known knots and chemists can only make one that's we know that we're beginning to show that we've got a bit more ability than that knotted structures are of course abundant in nature as we know there've got to be reasons for this and that's really the reason that perhaps it's interesting to make these kinds of structures because now for the first time we hope that it will be possible to look at the consequences of tangling of entanglement and topology and the properties of materials we hope and we'd be interested in collaborating on ideas of measurements that they might want to do on chiral or non chiral knots pulling with various things I see that other people are doing this at this meeting and so on so thanks very much indeed for having me these are the people who've done all the work, they're a real great bunch from all over the world and I'd like to thank them for their imagination, their creativity and their hard work you'll see many of them not from the UK and one of the big tragedy at Brexit is not the financial problems that it will bring to the UK or even the effect of funding on science it's not the effect of peace and stability that it could have on Europe but it's really the freedom of movement is the tragedy for the UK not just because we are allowed to attract some of the best young scientists to the UK but also because of the richness that it's brought to our culture and society for the last 40 years sorry to end on a bad note and I'd just like to thank you again for having me and I look forward to the rest of the time thanks