I'm Corin, CEO and co-founder of Rowan, and in this video we're going to look at global electrophilicity index calculations. Global electrophilicity index calculations are useful when you're trying to rank a bunch of electrophiles by how reactive they are. The conventional way to do this would be to actually draw out a model nucleophile, find transition states for reacting this nucleophile with each electrophile, and then rank the relative ∆∆Gs of these. Some reactions will have a high barrier, some reactions have a low barrier, and based on the transition state energies, we can actually predict the relative rates of reaction using the Arrhenius equation.
But there's also a lot of ways this process can be tedious or somewhat frustrating. Finding transition states is a little bit time consuming: it's not the simplest thing in the world to automate, and you have to run all these frequency calculations to make sure you actually found the correct transition state, and it turns out that for reactions with soft or covalent nucleophiles there's actually a shortcut we can use so we don't have to do any of this work at all and this is calculating the global electrophilicity index. The global electrophilicity index is just a function of the electronegativity and the hardness of the fragment in question and it turns out that over a wide range of covalent nucleophiles this value correlates really really well with the barrier to reaction. So if we're trying to design a warhead with a given reactivity, we can just do this based on the electrophilicity index and skip all of these tedious transition state calculations altogether.
Let's see what this looks like in practice. We can go to the “New Fukui index calculation” button here from the home page of Rowan and input a 3D structure. So let's actually just draw it out by SMILES, because that's a little bit easier in some cases, and we'll start by looking at this methyl vinyl ketone. We'll look at this because this is expected to be somewhat electrophilic, right? So we can do conjugate addition here and we'll say “Run new Fukui index calculation.” And although it's not listed, this will also calculate the global electrophilicity index over here. This is because these calculations use a lot of the same sort of machinery under the hood. And so we just group them together, so you get two for the price of one. Now, if we see what this is, this gives us a global electrophilicity index of 0.952 eV.
Now, this might not be the world's most meaningful number in isolation. So I'll actually go and compute a different value, so we have something to compare this to. And we'll go “resubmit as Fukui index calculation.” And now we'll modify this molecule, so we have some different substitution here. We'll make this now into an acrylamide—these are pretty common covalent inhibitors, and we'll edit this dihedral so it looks a little bit more sane, and then we'll say “submit Fukui calculation.” So this will optimize and run the calculation pretty quickly.
These calculations are very fast to run, so they're suitable for high throughput screening or an iterative genetic optimization, which is one of the nice features about them. And so now if we compare: our previous value for the global electrophilicity index was 0.952, and over here, we can go to the global electrophilicity index and see that it's 0.676. So this is quite a bit lower. And this makes sense, right? We've added an amide here. This stabilizes this a lot, this makes it much less electrophilic, and as a result, the electrophilicity has gone down.
Let's model just one more effect on this, perhaps. So let's now, we'll resubmit. We'll resubmit this again as a Fukui index calculation. And we'll now just throw fluorine on here. So this we expect will increase the electrophilicity of the calculation. And we'll say “with fluorine,” because I don't want to wade through that smile string again. We'll say “Submit Fukui calculation.” So we can imagine this in the course of an optimization. We'll say, okay, maybe this one was too electrophilic. You know, maybe this one wasn't electrophilic enough. So now let's add a fluorine and see, you know, do we think this will be more or less electrophilic than our starting compound? This would be a little bit annoying to take care of if we didn't have this sort of lovely instant electrophilicity calculator button here. And now we can see that the global electrophilicity is predicted to be 0.782 eV, so sort of nicely between our two previous compounds. So it looks here like adding the fluorine moves us up in electrophilicity, but it still doesn't quite take away the effect of the acrylamide. So maybe this would be a nice compromise compound for some covalent inhibitor or just for a synthetic building block.