When I picked up the JACS paper from Belowich et al earlier this week, I have to admit I got quite excited. Not only was this a collaboration between Fraser Stoddart’s lab in the US and Lee Cronin’s here in the UK, but molecules that seem to almost self-catalyse their assembly are very reminiscent of origin of life ideas, which I love. It’s interesting that using the same kind of interactions that biological molecules use, in fine balance, can result in this cascade that gives you much more complicated chemistry, and I couldn’t help thinking that this was an example of the chemicals outsmarting the chemists.

Favourable pi stacking interactions and hydrogen bonding allowed the researchers to get good yields of the polyrotaxanes © J. Am. Chem. Soc.

You can read my story here, but there’s only so much you can fit into a story, so below I’m pasting some more of the details from a conference call I had with Stoddart, Belowich and Ron Smaldone.

And Cronin? Well he didn’t make the conference call, owing to being tied up chatting to the BBC about some unrelated work, but he phoned me a bit later. His involvement in this paper was with the ion mobility mass spec, which proved that the pi-stacked rotaxanes were incdeed stiff, rather than flexible. But Cronin told me that this is just the start of a long running collaboration between his lab and Stoddart’s and the first of several papers due out soon. So as they say, watch this space…

Matt Belowich: The original intent of the project was to make these rotaxanes rigid and inflexible and we had maybe some inkling at the beginning that we might have some cooperative effects, just because of how we were constructing these using non-covalent bonding interactions and pi stacking, but we certainly didn’t suspect it at first and it was something we stumbled upon.

Fraser Stoddart: I think there was another driver, which was just how far we could go in terms of putting numbers of rings and associated numbers of reactions into place and get, in the beginning, acceptable yields. I was blown away by the fact that as Matt went higher and higher the yields maintained their awesome level and in some cases they seemed to get better. And so the fact that we aimed for a 20-rotaxane was just a round number. At Matt’s thesis defence a couple of months ago, somebody asked him if he could make a 50 rotaxane and I don’t think he hesitated for a minute before saying ‘Yes, it’s just a matter of a little more effort.’

MB: Absolutely, it’s just a matter of ‘Do you want to do it and do you want to put in the work?’ I don’t think there’s any question that it could be done.

It seems you were getting phenomenally high yields given the number of components…

MB: Yeah, that was one of the properties that fascinated us so much by this and I think it’s really a testament to the type of chemistry that we were using, which is dynamic covalent chemistry, which is performed under thermodynamic control. If you think about typical organic reactions, which are mostly done under kinetic control, you think about putting two or three components, maybe four at the most, in a reaction and getting, if you’re lucky, 90% yield. But because of our thermodynamically controlled reactions we can put in, in the case of the 20 rotaxanes I think 39 components and 38 reactions, and get these remarkable yields of 90% overall, which means each individual reaction is occurring in greater than 99.7% efficiency.

FS: I want to raise one thing. If you analyse the possible mechanism, which we’ve done in the presence of computational chemist Bill Goddard at Caltech… he reminded me that it must be remarkable from the point of view of entropy because you’re ending up with something that’s very very highly ordered. But the point is a route to it. If there wasn’t crosstalk between the rings, you’d expect them to be jumping around when the first one, the second one is on, the third one and that must mean that these intermediates must be pretty highly entropically favoured. And yet all of that seems to be overcome, presumably by the enthalpy garnered, as Matt points out, not only by the hydrogen bonding interactions that associates each ring with its charged centre on the dumbbell, but the pi-pi stacking interactions that come into play between the rings. One can just speculate, and we’re waiting on Goddard to shed more light on the reaction, that the rings might come on willy nilly to begin with. But my way of thinking of it is that they then cluster and that these clusters form the basis for the cooperativity. A bit like there are several cars on the road to begin with that are moving twowith some sort of velocity and then there’s a sudden acceleration.

It starts and then it reaches a tipping point and shoots and accelerates to the end point?

FS: I think it’s a bit like crystallisation in that it’s crystallisation in one dimension. If you draw the analogy then you can think that we’re as ignorant of the real details of the reaction as one is today about the process of crystallisation. You know, the editor of Nature back in the 1980s some time, Sir John Maddox, said that even at that time, and it could be repeated today, that we know little or nothing about that process. So I think that the last comment I’ll make is that this area of dynamic covalent chemistry – mechanistically we’re really in the dark ages, we are still just waving our hands. It’s nowhere near as developed as if it were a kinetic reaction and you could talk about S_N1 or an S_N2, or an E1 or an E2 or whatever it might be in terms of mechanism.

MB: We know what happens at the very beginning and what the outcome is but for everything in between we have blindfolds on. I think just looking at the mechanism of forming the 2 rotaxane, with just one ring, is difficult enough and you can imagine with 19 rings it’s just impossible right now. It’s very much an open area of research right now.

Ron Smaldone: My part of this project was to explain some of this using some basic computational chemistry. But what we found with the calculations was that there was actually a remarkable change when you went from the non-rigid type of rotaxanes, which are really only a couple of atoms or bonds longer in their spacing than the ones Matt made and the structure were remarkably different. I think it’s really cool that if you look at the interactions that are involved – really just solvent, hydrogen bonds and pi stacking as far as the non-covalent interactions go – it’s really similar to the way DNA assembles and if you look at a lot of studies of synthetic DNA you see that there’s a very cooperative type of assembly as well. It’s kinda cool, and it’s one of the things I really like about supramolecular chemistry, that you can use the same interactions that nature uses and it doesn’t really matter what the bones are of your molecule, you can still use some similar things with it. Matt’s molecule in some ways looks like a DNA but it’s really not at all like DNA, but its assembly properties are actually pretty similar, in some ways, to DNA. Which I think is remarkably cool and offers the potential to use the concepts of nature to make things that aren’t really like nature at all. You can never imagine using these rotaxanes to make synthetic life forms or anything like that but maybe you could use them as a really smart assembly for materials that use the same principle as nature but for a totally different purpose. That’s one of the things I thought was really cool, just very small changes in the molecule totally change its properties.

It struck me that you’ve got this very complicated thing and then it starts to self-assemble and self-catalyse. Are you going to look back and see other ways that things can cascade? Are you going to use this inspired approach to lead to different things?

FS: I think one is going to see more of this type of chemistry, more of this type of synthesis. As Ron puts it, it’s bio-inspired if you want to put it in that language. We tend to approach our chemistry based on a decade or two, or three now, of weak interactions being studied under the umbrella of supramolecular chemistry. But one’s never far away from the fact that when you make an observation such as Matt made with these bigger and bigger rotaxanes, that got almost easier to make, if you put aside the effort he had to put in to make the dumbbell. After that it was just zip, zip, zip to get these products. But I would like to put a note of caution – it took probably five or six years to get to where we are today. The interactions are very finely balanced and I think of the inspiring things was that Matt went back and looked at a piece of chemistry that had been published a few years ago and said, ‘Let’s reduce the space between the rings,’ and that’s what Ron was alluding to as well, to the point where we have this magic 3.5 Angstroms, the same stacking distance that you get between the bases of DNA, and see what happens. You can look back in retrospect and say we should have thought about this a bit earlier. It took us a little bit of time to work this out but once we got it, it just took off and the sky would seem to be the limit.

Laura Howes

                  

Source:
http://prospect.rsc.org/blogs/cw/?feed=rss2