If you think synthetic organic chemistry lacks innovation, then check out this episode where Paolo talks with Dr. Josep Cornella about the ways he and his team are breathing innovation into modern synthetic chemistry. Dr. Cornella’s non-discriminatory approach to catalysis has enabled him to do amazing things, including making air-stable nickel zero complexes and using non-traditional catalysts such as bismuth to open new doors and break away from established catalytic reactions.
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Modern synthetic chemistry relies on a rich toolbox of chemical transformations, among which catalytic reactions play a prominent role. Yet, despite all the many successes, innovation in the field has seemingly slowed down, the focus moving to exploring variations and application scope of well-established catalysts based on a limited number of reliable transition metals.
Josep Cornella, from the Max Planck Institute in Mülheim an der Ruhr, is an innovator. He is not loyal to a specific element or a specific catalyzed reaction. He has a non-discriminatory approach to catalysis, where the key is choosing the catalytic approach to do what he wants/needs rather than figuring out what he can do with his catalyst of choice.
This episode is a declaration of love for catalysis as a driver for innovation in organic synthesis. Paolo and Josep discuss using the elements the Earth has given us in creative new ways, from making air-stable nickel zero (Ni(0)) complexes to the unexpected use of bismuth as a completely novel catalyst, opening the box of possibilities by removing the biases from overreliance on well established – and old – concepts.
Dr. Josep Cornella 0:05
I attended one talk. And he said, that the Earth has provided with all the elements of the periodic table, just go use them. And that was that was like a funny comment that he did and but it kind of got stuck in my head somehow.
Paolo 0:19
Josep Cornella has done some of his best work when he's thinking outside the box. One of the most important tools in his work as a catalysis specialist is his curiosity. With it, he and his team have discovered more than they could have ever expected. In this season 2 episode of Bringing Chemistry to Life, we speak with another member of Chemical and Engineering News' 2020 Talented 12 about their work and trends in their field. I'm your host, Dr. Paolo Braiuca from Thermo Fisher Scientific. We began by asking Dr. Cornella about how organic synthesis kick started his scientific career.
Dr. Josep Cornella 1:03
So organic synthesis was the subjects at the Bachelors level that I was, let's say, most good at, because I really liked it to study. I was not bored studying that stuff, disconnecting molecules, connecting things together by really beautiful arrangements and rearrangements and stuff like that, right. It was very intuitive to me and it was not very difficult. But obviously at the Bachelors level, these get harder and harder, right. And, at the end, my whole thing has been organic synthesis, but never like hardcore, or synthetic organic chemistry, like total synthesis, or you know, or stuff like that it was then I discovered catalysis. Catalysis opened my eyes in the sense that is like, okay, I can discover new ways of making molecules not, not just making the molecule at the end by whatever means. But I can probably find a way that nobody has found before to connect two different entities or three, or four, or whatever. And that was really kind of eye opening. And then I always pursued that down the path of homogeneous catalysis. And that brings a lot of areas together, right, organic syntheses, organometallic chemistry, a little bit of inorganic chemistry coordination. And we fall under the umbrella of organic synthesis, but we are a mixture of a little bit of everything.
Paolo 2:24
There's another one, the other one thing you said that I really liked is your liking catalysis, because it gives you the potential to do things in a different way or right out or do or to do new things that no one that no one else has been able to do before. Can you can you comment a bit more about that?
Dr. Josep Cornella 2:43
So is, this definition that you just gave is the most difficult one to come up with something that nobody ever has done before, it's very, very complicated. What you can come up with this new ways of doing things that resemble something by reading a lot, by reading a lot, and realizing that this, the reactivity of these elements, and these systems could give you, you know, interesting, interesting reactivity for, I don't know, the breaking, it breaks a bond, you know, that you are very interested in, and then all of a sudden, you start thinking, Okay, if this breaks, then maybe I can design a way, you know, a catalyst that could break this bond and then engage in these other molecule. And then therefore, the final product is something that maybe nobody has done before. It's not that we are trying to invent completely new reactivity or new rules for chemistry. But what it gives you the opportunities is to draw yourself to molecules that you would never think that that that nobody has probably put together, right? And then you go, wouldn't it be nice to connect to disconnect here and disconnect here and put this together? And catalysis is a very powerful tool to do that. And I think that is what what really, really allows you is a really enabling technique. You know.
Paolo 3:56
A lot of the catalysis people I met in my life, they were really in love with their metal systems, right? You typically find a palladium people, a ruthenium people. And you know, they immerse themselves in the in the chemistry of the metals in this organometallic chemistry aspects around it. And then you somehow produce a number of studies that are looking into different aspects of the same sorts of chemical species in the origin. Here, you're telling a different story, right? You're telling a combination of sorting out of fixing up a synthetic chemical problem.
Dr. Josep Cornella 4:38
And this approach is a little is it's a high risk, high reward, I guess. Being a from the catalysis and not from the organometallic part, I think what it brings a little bit is to be naive. And I don't know how to say it, but like if you know a lot, a lot, a lot, a lot of your system that means that you know a lot of a lot, a lot, a lot of limitations, and therefore that is going to prevent you probably from designing things that you already are biased by the fact that they will not work, right. And therefore, what happens is that, then you will never set up that reaction that might give you the surprise. And this is what sometimes, I'm not advocating for advocating for knowing little. But what I'm saying is that sometimes jumping in an area, certainly, for example, for us in the bismuth area, we had no idea about bismuth before. But then at the end, I think that the original idea that was completely naive, if you had talked to somebody that was truly organometallic that dedicated their time and life to an area of chemistry probably didn't even think about it, or, you know, like, discard it for some other reasons, and so on. And this positivity of naivety is quite this quite interesting. If you know a lot, then the difference for you, between a methyl and ethyl is like the most important thing in the world. Whereas if you zoom out, the difference between the methyl and ethyl, most likely is there's gonna be very little influence. Right? And, and therefore, like, having an overall big picture is very, it's a difficult thing. I think.
Paolo 6:14
This comes across very, very clearly from your studies, in my view. There's an interesting story. So let's pick up more about your bismuth. Can you can you tell us a little bit about what it is how it works? What, why it is important, what you learn on your journey about it.
Dr. Josep Cornella 6:28
This comes back to when I was a postdoc in Catalonia that I had, I attended one talk from Mattias Driess an inorganic professor at U. Berlin. And, and he said, the the Earth has provided with all the elements of the periodic system, the periodic table, just go use them. And that was, that was like a funny comment that he did, and, but it kind of got stuck in my head somehow. And then I went to another GRC conference in the US when I was during this time, also a lot the same time and, and there I remember, Professor Silas Cook from Indiana University. He was presenting, and he was talking about sustainable catalysis. And he had like a picture of the elements that were considered sustained, sustainable elements. And he had iron, he had cobalt, manganese, chromium 2, copper, and bismuth. And when he put bismuth there, I was like, no, no, sorry, but I think there's a mistake, it must be like a B for an N, right, of nickel or something. And I went over to him after the talk. I said, like, dude, you put here like this. Okay, yeah, check it out. I mean, it's like really benign. And so there is a lot of reports bismuth trichloride, bismuth triflate. And it's considered to be like, non- toxic and so on. I was like, well, and that was like, I think the moment where I got interested in these guys like, okay, let's look into this. And I started reading and reading and reading a bit more. And then I found what I told you, right? These are stoichiometric experiments where people was using bismuth 5, that would go to bismuth 3, and so on, but the stochiometric, and then it's like, alright, we just need to bring back the three to five and we close the catalytic cycle, right? And we wouldn't be able to develop that, then there were some hints that this would be possible. And then when I got the opportunity to come to them explain, okay, it's like this is the place to do it, because it's about always all about fundamental chemistry, fundamental reactivity, and catalysis, the Max Planck Institutes are for fundamental science. And if there is application great, but it's just to study fundamental research. So I said, Okay, I'm going to propose this bismuth. And, and here is where it started, right? We started working on this I hired very talented PhD, then a postdoc, super talented postdoc came in, and they both did a great job. And now we have I don't know, six, seven people working on just bismuth catalysis.
Paolo 8:43
And it works, right? It works, you managed to close that catalytic cycle.
Dr. Josep Cornella 8:47
Yeah, exactly. So yeah. So it could have been a dramatic failure. Right. I mean, let's face it. But I, there was evidence that that could be possible. And then we applied it in two different manifolds, what what we call the low valent manifold, which is the one-three redox cycle. And we use the three-five redox cycle, which is the one that we've been able to do with aryl triflates or aryl fluorides, and so on, which is the most recent work, I guess.
Paolo 9:13
So I'm going to give you a challenge now, because it's very difficult to do without any sort of visual aid, right? But you started from the, from the bismuth three to five, a kind of redox scaffold. And then you had this idea of closing the cycle. How do you go along with closing the cycle? What, how does your system work?
Dr. Josep Cornella 9:31
This is another thing that differentiates from transition metal catalysis is where you just mix ligands and catalysts, and you can serendipitously like find the right combination at some point if you extreme enough. This is completely different. Because you need that you can not just put ligands that work for transition metals into bismuth and pretend that they are going to coordinate in the same way that they are going to do the same thing that you want and so on. So what we had to do is to really dissect everything and go to the basics, okay, we want to do a catalytic cycle that is going to have three fundamental steps. And these fundamental steps are all stoichiometric, right? By definition, right. So we're going to analyze every individual step and make it quantitative. If we make every step quantitative, like if we can prove that all these steps are working, then maybe we have a chance. And that is what how we started how we approach this. So we start from bismuth three, and what we need to do is to introduce an aryl group. So we investigated that turns methylation event into bismuth three that was not known. Then after that, we need to find an oxidant to bring the bismuth three, which the lone pair is very contracted, because it's the last group in the group 15, and is the last stable element in the periodic table. So it's like a huge cationic core. So we came up with this fluoro-peridinium, that just oxidizes the bismuth three to bismuth five fluoride. And then the reductive elimination had to happen. With react, all these rules change. We call it oxidative addition, directive elimination, but when you move from traditional metals to main group elements, the geometry is the symmetries and the orbitals that you play with, they are not D, they are P and S. So everything changes, you have to relearn everything. And that's why we had to go to the very fundamental steps and design the proper ligands. It's quite interesting fact that that we can do these redox catalysis, three, five, right, with an element that is not a transition metal. That is a that is I think the fundamental cool thing.
Paolo 11:30
So for the benefit of our audience, the transformation uses a model reaction was the conversion of boronic acid into triflate. Right?
Dr. Josep Cornella 11:40
That's the one, yes. That's the second one. The first one is the boronic acids to aryl fluorides.
Paolo 11:43
Okay.
Dr. Josep Cornella 11:44
Yeah, to fluorides, which are, right, it's interesting information for medchem and so on.
Paolo 11:50
Do you foresee the system having a real commercial, even commercial application in the future? How far are we for having a robust catalytic platform that can be used, you know, for for a lot, a lot, at least some useful transformations?
Dr. Josep Cornella 12:07
Well, this is the this is the beautiful of this, right? That is very hard to do to be very hard to predict. It's it's unpredictable. And the fundamental chemistry is what it has. And and I want to I want to mention that I think it was professor Marina talk, that he asked himself and to the audience. What is important? And I think it's it really boils to the point like Buchwald Hartwig amination when it was invented, I think they were using stannane amines that was the origin of a revolutionary kind of reaction for for so many applications. But I'm pretty sure that if you had asked back in the day to these guys, this is gonna be I think it depends on how many people like is going to jump into this topic also, that is going to help it do it better. If they are interested, if not the price of this motif, it's really benign, or if it's cheap now, because it's a byproduct of another element that nobody wants to use. I think there is a lot of factors, it's certainly the idea that we have is not to replace transition metals. So that is an important. So we want to mimic transition metals in terms of reactivity. But we want to provide reactivity that goes beyond the transition metals that is orthogonal. And this reflects, for example, converting boronic acid to a triflates is a reaction that you cannot do with a transition metal. A triflate anion as a nucleophile is very, very strange for a transition metal, right? You usually put a triflate to generate back end sides to not do interact with their metal center.
Paolo 13:41
Yeah, so absolutely, you're gonna use counter ion in your complex.
Dr. Josep Cornella 13:44
in some sort of metal cationic complex, and then and then for some reason, bismuth brings it into the coordination sphere and couples it to your aryl group. And that I think is conceptually new.
Paolo 13:54
And that is good, because if I look at the chemical space, particularly in the pharmaceutical development, you know, I think it's fair to say that we are limiting the exploration of the experimental space because of our over reliance on a relatively small number of extremely effective transformations, right, that are used over and over again. And, you know, the Buchwald Hartwig is one of those now, right is is maybe that the newest of the of the bunch have been a you know, if you look at lots of biaryl systems there just because it's so effective, right, you can do it, and it's so well understood. And this is also why some people are saying that there's very little innovation going on in organic synthesis, which is a bit of a disappointment to me. So So do you think we need more innovation in in in the sort of synthetic tools?
Dr. Josep Cornella 14:53
I certainly think so. And I am a big advocate that we are far from like being good. That still one of the bottlenecks in discoveries is still the organic synthesis part. So we need to come up with more strategies that tolerate functional groups that are not limited by functional groups, like they have a lot of nitrogen atoms, all these drugs, they have a lot of polar OH or NH bonds that interact with transition metals that will destroy them, and so on. So we need to find out still a lot of technologies that are orthogonal and highly selective. I think this is one of the research lens in my lab, really what I told you about that we have this pyrylium chemistry, that what that allows us to convert amino groups into a leaving group, which is designed this pyryliumthat grabs very selectively these amino groups, and just by the addition of a nucleophile just kicks out pyridine and put your nucleophile where you want it. And it's very selective. And these are very practical method, right.
Paolo 15:52
We hope you're enjoying this episode of Bringing Chemistry to Life. Did you know you can register for a free Bringing Chemistry to Life t-shirt? Stay tuned at the end of the episode for information on how to request it, and also how to access interesting content recommendations from our guests. And now back to our conversation.
I'd like to go back to catalysis and that's when your work on the nickel catalyst systems. The tricky part of of using nickel despite the interest, right, of the organometallic community because you know, you can avoid potentially the use of precious metals and then things like that these days, it's not easy to handle right? It can be pyrophoric, you know, so you actually found, you found a way to an air-stable nickel catalysts seem to be working very well. Can you tell us the story there?
Dr. Josep Cornella 16:49
So this story is also a little bit about it would be great if we could. I've been working with nickel COD for many years first thing in Spain in the Ruben, in Ruben Martin’s lab, and then in the Baran lab and, and I always had this impression that nickel COD is the is the only guy that is available. And I always wonder if somebody could do nickel COD air-stable, that will be absolutely amazing. No, because it's a pain to go into the glove box, not everyone in the world has access to the glove box. And on top of that there is a rich chemistry of it. There are a lot of transformations that are only catalyzed by nickel COD. And I thought that that would be a game changer. And there has been many people that looked into making air stable precursors of nickel zero. Yeah. And and the idea here was to my student that was working in in related very low valent formal nickel minus two project like, we're always talking if we could make these and that and so on. And then by looking at the mechanism of transformation completely unrelated to this, when he dismantled the whole setup after the filtration, in one of the cases, he didn't see that when you remove the argon, everything goes to nickel black very rapidly. And you can clearly see it. Yeah. And he realized that he was staying as red as your jumper. And he was like, well, that's weird. And that's new. Right. And I think here was one of the key moments when you have the student that because we talked about the potential. And he knew that all the background of you know, he realized that maybe that was something important. So when he was washing a filter, and that is and that is the I think the chemistry intuition that comes that comes to that comes to light.
Paolo 18:30
So serendipity brought you to this discovery?
Dr. Josep Cornella 18:33
It brought me to this, but we already had the idea of of kind of if we could, right? But we were always obsessed with 18 electron, we always had the idea, it has to be an 18 electron, because these are novel configuration, and you know, and so on and so forth. But this guy now is a 16 electron, which they are all extremely air sensitive. But this guy is not. And that was like very puzzling to me. And we just saw he brought with a vial like one gram and a half hear in my office, like, do it now. This is crazy. So we started doing analysis and more analysis. And still, I must admit that still today, we don't understand it. We don't understand it. So, we have we crystallized I think five or six different ones and its always the same structure with a nickel surrounded by three olefins that kind of wrap around the metal center. But when we try to do an NMR of it, it's never this it's something else and it's very strange behavior in solution and but it's fascinating right? Because we know by elemental analysis that we have three ligands and one nickel, that is clear. We can repeat these elemental analysis and it's always telling us the same three to one ratio. Now the question is if the arrangement it could be that when you try to crystallize it, it this is the preferred confirmation, but when you have it as a powder, there is something else, you know, and and that's why we are now working and see whether it really is this thee olefins, or it could be something else, you know?
Paolo 20:07
Can you tell us about how it behaves? Is it, is it, behaving very, very similarly to the the standard nickel DOD, what can you do with it?
Dr. Josep Cornella 20:15
So what we can do in the first article, what we did is we have two stilbenes, right, the stilbenes are the ligands, and the stilbenes are substituted at the position four, and at the very first generation, let's say you had CF3s and CF3s were the ones that, you know, we were relatively air stable. But when we would dissolve it in THF, complete destruction and in nickel black immediately. Unless you had a supporting phosphine in it. Like if you had an NHE or a diamine, I mean, it would rapidly make the complex and that complex would be stable. But in spite of that, we could catalyze a lot of reactions that nickel COD could catalyze in the same kind of level of reactivity. But we had a bunch that would not do anything. And then what do we have that nickel COD doesn't have is a good platform to tune the electronics on these ligands that probably will affect not only the physical properties, but also the chemical properties. Because if you if you think about it, if you have three olefins, and you are the diphosphine, two olefins will go but the third one will stay. And the second one, the electronics on the stilbene can tune how fast or how not fast, it's going to dissociate up from the metal center. And look, I said, Okay, so I'm going to start putting electron donating electron withdrawing differences, the two ends and so on. And then he found that this with this tert-butyl, that he was the the reactivity was extremely fast, the physical properties were incredibly high, so we could store it under air for at least a week, then it starts getting, we don't we don't have to forget that, in theory is a 16 electron complex. So it's air stable they will but it's better if you store it in the fridge, under Ar not air.
Paolo 21:58
It's interesting, because you, you got there in a very original way. But then you started doing what seems like more traditional ligand design, and then you you slowly improve your your system.
Dr. Josep Cornella 22:10
Yeah, by serendipity, we stumbled upon it, and then was like, Okay, now we have a system and we have a platform that allows us to and we have a good way of making them, which is using the old Mulheim recipe from Gunter Wilke, the former director here, with aluminum salts, and and they just crash out. And yeah, so we licensed it and we just when we saw that it could catalyze. Now, when we put this tert-butyl. Sorry, I forgot to mention that when we replace the CF3's for these tert-butyls, all those reactions that we could not catalyze. Now, they were catalyzed by this one because the electronics is not electron withdrawing is more electron donating and the COD ligand is a little bit of an electron donating ligand, so it resembles more to the reactivity of nickel COD.
Paolo 22:57
What's next in these lines of research, we have been speaking about, you know, the bismuth, the nickel catalysis, or even the palladium salts, what is what is now your focus?
Dr. Josep Cornella 23:07
In the pyrylium reagent functional group type of stoichiometric chemistry, organic synthesis, I would say the idea is to push this chemistry to substrates there is no other way to deaminate, let's say. And that that is one area that we're we are looking at now currently, and the bismuth, the the idea for the bismuth is to consolidate it. So now we had the first three shots, right, in which we demonstrated bismuth one and three redox catalysis and three - five is both possible, but we need to consolidate. My idea at least is to consolidate these as as, as an approach right the bismuth redox catalysis we need to provide at least as much as we can in these areas to be able to say okay, this is this is a thing is not just a boutique example. And I think providing more bismuth one-three and bismuth three-five redox platforms, I think it's I think it's the way to go here. And then we started a new area and this is within the bismuth there is a new branch that is that is quite cool that I cannot comment on more, but it's also exploiting the redox chemistry of it, but completely new type of redox chemistry, I think from my perspective, and I think it's very, very exciting. And I, I wish I could tell you more about is it still a little bit on the like very fresh and very new over that. That's why I'm talking very excited about it because it's very new and is very interesting and, and the nickel chemistry basically, I think, I think it's understanding what I just told you these these strange behaviors. Because once we understand this, we can go so maybe we have to take a step back. Now we already put them out there people can use them. But now, I think we should we have already a structural evidence and so on but now we should I think focus on understanding it and, and provide as much information to the to the users as possible about coordinations and things like that.
Paolo 25:09
And he makes sense based on all, all all of our discussion today, you know, you're jumping between the the application aspects and the fundamental understanding that will allow you actually do prove application. And it's almost like you're your own research catalytic cycle, right? That you need to keep to keep to keep to keep running.
Dr. Josep Cornella 25:28
Exactly, yeah.
Paolo 25:29
It's amazing. Listen, as we get to the, to the, to the end of our of our of our chat, you know, I want to touch on on one aspect that I typically always get at the end of my interviews, and you mentioned, a lot of a lot of times, you know, what, while you were discussing your examples, you know, the input for from a lot of talent in your team, you know, you know, you you mentioned a lot of your student PhD's and postdocs. And so this this is this is really key. And I guess you're embracing your role as a as a team leader here, right? So how was for you this transition between being, being, just being a scientist on the bench, and then, you know, growing into this role of enabling other people to deliver results and giving them ideas, but also leaving them the freedom to explore, right? How do you how do you handle that?
Dr. Josep Cornella 26:22
It's quite complicated. Because I always say the same they hire you for because you're good in the fume hood and solving some problems or something. And then they just like a crane takes you and puts you in an office and tells you here is this group, just to start hiring people, and it's like, excuse me? How did this happen? And the idea for me at the very beginning, and it wasn't advice that I got, it was not to rush to get the lab full. Just take your time and get the right people. One important thing for me, at least when I started was I need to be surrounded by people that know more than me, that is very difficult to go after these people, especially for some that they want to come with you that nobody knows you, there is no safety net, they might jump into a completely black hole. And so, and I was fortunate enough to to recruit really talented people, and that made everything. So the whole bismuth chemistry was the intellectual plus the hard working and the motivation of like the first the first guys especially the first the first two students, right, these two guys started this area point like, out of with, with a boss that we had to relearn everything all together. Right. And that was quite, it was very intense, but very, very successful at the end. So I'm very grateful. And these guys were really, really keys for for developing this. And then all the people that came came after the second generations are incredibly amazing also, and they are keeping up the level very, very high level. And also in the nickel chemistry. First PhD student realized about it, just buying it on his own, with the help of a technician that we have here, very talented technician, they together, they just did everything. And then they joined another master's student and so on. But I'm really grateful that they jump into these completely bold ideas and they contributed so much. I mean, it's, it's great.
Paolo 28:30
You've been fortunate, right with meeting a lot of smart people and you've been good in keeping keeping them with you and and you know, supporting them in their endeavors. And you're probably also being good in applying the good advice you have received, by someone telling you you need to you need to hire people who are better than you. And then you know, you, you you working on this course, and actually making a strength out of it is, is is great. And that's what leads me to my final question there. Now you have gone through all this. If you look back, what will be one piece of advice that you will pass on to young scientists who are not as advanced as you are now where they are just starting their career.
Dr. Josep Cornella 29:11
Just be passionate about what you do and try. Don't be afraid of going completely outside the box outside your comfort zone. You're gonna face areas of scientists that you didn't know before. And to do that, make sure that you get the right like the good people and just treat them well. Right I mean, that's that's that's all it is. At the end, this is a whole team, it's not an individual thing and if you'll see the publications there is, I'm not alone, right? Go after people that are that are motivated. This is the most important thing and, if you, if the person is motivated, it's more, it's 10 times better than knowing a little bit more. And try to not to be the person that knows the most. That's also another thing that helps me to motivated to come and learn every day. Because if you are the one that knows the most here, I find it, what's the point of all this thing you'll have to surround yourself you have to challenge yourself, right? Surround yourself by extremely good people that have different you know, expertises and then we can put them together and do stuff that that's that's the idea.
Paolo 30:32
That was Dr. Joseph Cornella, Group Leader at the Max Planck Institute, and one of the Chemical and Engineering News' Talented 12. Thanks for joining us for this season two episode of Bringing Chemistry to Life, and keep an ear out for more. If you've enjoyed this conversation, you're sure to enjoy Dr. Cornella's book, video, podcast and other content recommendations. Visit www.thermofisher.com/BCTL to access these recommendations and register for a free Bringing Chemistry to Life t-shirt. You can also find the URL in the Episode Notes on whatever app you're using for listening. Have a look. This episode was produced by Matt Ferris, Matthew Stock, and Emma-Jean Weinstein.