Dr. Mark Szabo: NMR Spectroscopy. Challenges in Structure Determination, Thermodynamics, & Kinetics

Foreign.

Welcome everyone. Today we have the opportunity to hear from Dr. Mark Szabo who's joining us actually all the way from Hungary. Again sort of that a global outreach of Emory Pharma. But yeah, I'm going to introduce Dr. Szabo who received his PhD from Yotfos Lorand University in Budapest. Again I'm going to do my best on the pronunciation, so I apologize to anyone if I mispronounce anything. But through his education he had the opportunity to focus on several different NMR projects including structure and dynamics of Borane organocatalysts and some of their interactions. Following his education, Dr. Zavos worked as a researcher at Zemo Hungary Ltd. Where he led analytical efforts really as an NMR specialist, but as an avid researcher. One of his educational achievements includes developing the first online elearning graduation prep chemistry course in Hungary through the Level Me Up Lvl Meup HU prep course. So again expanding sort of that educational outreach. Currently Dr. Szabo serves as an Application Scientist at Chemaxon Limited where he works collaboratively with end users, sales and software development, including Chemo Informatics. He's also serving as an Emory Pharma consultant, primarily as our NMR specialist. Today we have the pleasure to listen to his presentation titled Challenges in Structure Determination, Thermodynamics and Kinetics. So please welcome me in joining Dr. Szavo.

So again thank you very much for the kind introduction. I hope you can see my screen. Yes. Today I'm going to introduce you to four short stories about the application of NMR spectroscopy. There will be some tweaks, how certain structures can be determined and also how certain thermodynamics and kinetics parameters can be found hidden in the NMR spectra and which can help us understand certain systems. So these four short stories will be the determination of the configuration of symmetrical geometric isomers so we can determine whether it's a Z or E configuration. The next one is going to be how certain auto activating metathesis catalysts could be developed with the help of NMR spectroscopy. The third one is going to be the dynamic systems of frustrated Lewis pairs. And here the emphasis is on dynamic. So I'm going to tell you how dynamic systems can be studied by nmr. And the last chapter is going to be the determination of the relative configuration of certain dirodium complexes. So these are the four short stories I'm going to talk about. So the first chapter, the first short story is how symmetrical geometric isomers or the configuration of these can be determined by nmrs and to Introduce you to the problem. I'm going to show you two molecules. Everyone is well aware of these molecules, maleic acid and fumaric acid. And this is the trans and CIS form of kind of the same molecule. So these are geometric isomers. And in this case in the NMR spectrum, one would see a singlet or a singlet like peak for the blue and the red protons, since there is no other protons which are coupled to these. And of course these are not singlet, these are just singlet like peaks because these are magnetically non equivalent protons. But what you would see in an NMR spectrum would be a singlet for malaic acid and the singlet for fumaric acid. If you know the chemical shift from the literature, for example, then you can decide which one is in your sample. But if you don't know it from the literature, then you won't be able to simply figure it out based on the chemical shift. The other thing is that there is a J coupling with the carbon atoms and there are 1.1% of the molecules where there is a carbon 13. I'm going to switch to the laser pointer. A carbon 13 present in the molecule. And in this case actually the two protons, the two blue or the two red protons are not chemically equivalent anymore. And these protons are represented in the satellite peak, the 1.1% satellite peak. And actually this three bond coupling appears between the two blue or the two red protons and you can figure out whether it's a cis, so whether it's a maleic acid or whether it's a fumaric acid based on the coupling you see on the satellites. This is actually a well known fact in nmr. So I haven't said anything new so far, but here comes the more interesting part. So the company whom I was working for, Czimo, was specialized in the synthesis of metathesis catalysts, with the help of which the Z homodimers alkenes could be synthesized with metathesis reactions. But here you can see the Z and E isomer. But in this case, in these homodimers there is a problem, namely that we have methylene groups connected to the Sp2 carbon atoms. And these methylene groups couple with the blue or the red protons. And therefore it's not that easy to read this coupling constant from the satellites, as you will see. But what we can do is there is a technique which is called homo decoupling or even more sophisticated techniques, which is pure shift nmr. And with the help of these techniques we can decouple these methylene protons. And what you can see here is actually the signal of this blue proton here. And you can see that it's a triplet like peak because of the couplings with the methylene protons. Actually these are just the starting material. It's not that important. It's the middle peak we are focusing on. And when I apply this Homo decoupling technique and decouple the methylene protons, I will get a very nice cingulate. This is the same molecule giving rise now to a singlet. Why is this interesting? Because if I zoom in to the satellites which can be found here, you can see that in the proton spectrum there is basically noise. You are not able to read any kind of information. But in the Homo decoupled spectrum you, you can see a very nice splitting, which is 10.6 Hz, which means that in our sample there was the isomer which had the configuration of Z. And we can go further because now we know where the signal of the Z and the E homodimer is, but we can quantify them and we can tell the ratios of the products in a metathesis reaction. And actually I could represent this Z configuration with this emoji. And this is the Z, sorry, the Z configuration with this emoji. So if we work with a regular catalyst, then there will be two peaks, two singlets. This is already a Homo decoupled spectrum and we already know that the left one is the E and the right one is the Z configuration based on the satellites. And actually we can tell the ratio. Right now it's 76% E and 24% Z, which means kind of a thermodynamic equilibrium. Actually, without Homo decoupling, I wouldn't be able to integrate these two peaks because these would heavily overlap. And when using the company's catalyst, then actually we can get 95% Z configuration in the end. So this was the first chapter where I used Homo decoupling to be able to differentiate between Z and the isomers of homodimer alkenes. Actually, I think there is no other technique with which you can figure out the configuration. So definitely LC Ms. Or GC Ms. Wouldn't be able to do it. If you have the Z configuration and you know that it's the Z, then you can measure a retention time and then you can use lcms or gcms. But to figure out which configuration is there, you need an. Mr. Let me go ahead to the second chapter, which is about how certain so called O2 activating metathesis catalysts have been developed at EXIMO. Actually these metathesis catalysts can be used to create those homodimers I been talking about. So let me introduce you to these structures. First of all, there are well known 14 electron shock complexes which are very effective catalysts in metathesis reactions. But the problem is that although they are very active, they are not very stable. They are air sensitive, they are moisture sensitive and it's very hard to work with them. And what Furstner did, he's a researcher in the field of metathesis, is that he created 18 electron adducts with the so called phenanthrolin which are not active anymore, but are stable. And actually phenanthrolin and therefore the 14 electron complex can be liberated with additional Lewis acids, like for example zinc chloride. This is actually a one way reaction. It's not an equilibrium system. You can see a very, very high equilibrium constant. So basically it's shifted to the right. And what we did at Casimo was that we used tungsten complexes instead of molybdenum, which are a little bit weaker Lewis acids. And we used B pyridine ligands instead of. And what we gained is an equilibrium system. Here you can see the equilibrium constant of the system. So actually we made these complexes, these 18 electron complexes auto activating because if you put them in solution they will automatically dissociate and the active complex will be there to do this, to do the reaction for us. And one driving force behind this dissociation can be that actually this antipelyplanar form conformation of B pyridine is way more stable than this one on the left. So this can be a driving force of dissociation. And what I did here with NMR is actually I made several one dimensional proton measurements at different temperatures from 25 to 70 degrees. And what you can see here is that here is the signal of the free complex. So the free 14 electron species, this is actually kept at constant intensity. But as you can see when we heat up the sample there is less and less complex 18 electron species and the system is more dissociated. And actually this is what we expect when we heat up a complex that it's going to favor dissociation. But actually by integrating the complexed 18 electron signal and 14 electron signal, I can calculate based on this very simple equation, I can calculate the equilibrium constants at each temperature. From the equilibrium constants I can fit a very nice linear. And the parameters in this linear is actually the enthalpy change and the entropy change from which I can calculate the Gibbs free energy. And actually I did this for several compounds. And this is a very nice thermodynamic parameter which can tell you actually how these systems are going to work. And actually, for example, what amount will be in the dissociated form at a given temperature. So these are very nice properties, what you can calculate from simple one dimensional spectra. And actually again, there is probably no other technique with which you can calculate such properties that easily and in such an elegant way, I would say. So let me jump to that third short story which are the moisture tolerant frustrated Lewis pairs. And again, let me introduce you a little bit to the topic and let me start with what are these frustrated Lewis pairs? Actually these are Lewis pairs where there is a steric hindrance, so there is a bulky Lewis acid and a bulky Lewis base. And, and therefore these are high energy systems, meaning that they can be used to activate small molecules and catalyze for example hydrogenation reactions. And one well known Lewis acid which is used in the field of frustrated Lewis pairs is this three spent a fluorophenylborane. And again the problem is, just like in the former case is that it's moisture and air sensitive. And our solution again was that we should create weaker Lewis acids. And how we reached this is that actually we decreased the number of the hologen atoms on the rings. And you can see that we synthesized three boranes. And in the first case there are three fluorines and three chlorine atoms in the system, all of them in the ortho positions. And then there is a ring which has two chlorines. So there is only two fluorine atoms in this borane. And in the last one there is only one fluorine atom and two rings containing two chlorines in the ortho position. And what we did is that we tested all these three boranes in the reaction. What you can see on the screen and the interesting part of this reaction is that this is a reductive amination reaction and one of the products is water. And if you remember this is a moisture tolerant catalyst or at least 3 spent a 4 of phenylborane was and we applied 10 mole percent of the catalyst so actually 10 times excess was formed from water. And here you can see in the table the results of the test. And actually the first molecule with three fluorines performed pretty well. We can call this well at 80 degrees in 72 hours the conversion was 78%. The second one, which had less Fluorines and more chlorines performed even better. It was 99% the conversion. And the third one performed just as well, it's 99%. But as you can see, it worked even when there was no molecular sieves in the system. So you can clearly see that there is a difference in the efficiency of the catalysts. And we wanted to understand what's behind this difference with the help of NMR spectroscopy. First of all, what we did is that we put in our sample the borane, the non coordinating Lewis base and some water, and we cooled down the sample to minus 30 degrees. And actually there is a very interesting thing here. You can see that the two protons of the voter give rise to two different signals in the NMR spectrum, one at around 4 and one at around 13. And then I thought that I should measure a DOSY spectrum and the result of the dosy spectrum, what you can see on the Y axis here is actually the diffusion coefficient of every species present in the sample, which is related to actually the size of the given species. And what we can see is that the two protons of water, which can be seen here because on the x axis you can actually see a hydrogen spectrum, a proton spectrum. So the two water signals, the signal of the doppcool, the base and the signal of the Lewis acid, the borane, all have the same diffusion coefficient, which means that they are connected to each other, they are coordinated to each other. And to prove that.