Henri Kagan's 1986 discovery showed that a catalyst's chiral purity does not translate linearly into the product's chiral purity, overturning the prevailing assumption that a 60-40 catalyst mixture would simply yield a 60-40 product mixture. Kagan proposed that a metal atom in the catalyst recruits two chiral catalyst molecules at once, so a starting mixture of left and right handed catalyst units combines into three types: left-left, right-right, and a mixed left-right pair. Because the mixed pair turns out to be catalytically inactive, only the matched left-left and right-right pairs do the work, which pushes the product's handedness ratio far beyond the starting catalyst ratio, for example from 25/75 up to roughly 10/90. This nonlinear amplification was demonstrated in the Sharpless epoxidation of geraniol and published in the Journal of the American Chemical Society in 1986.
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The combinatorics work out to about 6.25% left-left, 56.25% right-right, and the remainder as the mixed left-right pair, starting from a 25%/75% catalyst split.
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The reaction studied, Sharpless epoxidation, builds on earlier asymmetric oxidation work by Barry Sharpless, who won his own Nobel Prize in 2001.
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The hosts note the effect is multiplicative rather than additive, which is why the relationship between catalyst and product asymmetry curves rather than just changing slope.
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Kagan's finding addresses only the 'nonlinear effects' half of the Nobel citation, with Kenso Soai's work introduced as the next piece of the discovery.
1,266 words · auto-generated from the episode video
30:30So, I think we now are getting to our Nobel laureates. We know the setup and as a fan of Thierry Henry, the French footballer, although he was an Arsenal player, this is a Chelsea house, we will start with Henri Kagan. And so, what was it that he discovered as a part of now this setup we've created? Right, so now we get to our actual Nobel laureates. Henri Kagan tries to tackle the nonlinear part of the Nobel description, okay? Let's suppose that we start with a pure right-handed catalyst that favors right-handed products,
31:13right? Mark Wald has already shown that, that if you start with the catalyst itself has a particular geometry, then the products are gonna favor some particular geometry. Okay, so let's say the right-handed catalyst favors the right-handed product and the left-handed catalyst favors the left-handed product. The prevailing wisdom at the time was that if each of these catalysts work independently, then if I start out with, let's say, a 60-40 mixture of catalysts, the ending reactants are also going to be 60-40 because 60% of the catalyst created the 60% products, the 40% of the right-handed stuff created the 40%, then the ratio is going to remain the same, right?
31:55The slope in this case is going to be one. Like if I start out with some ratio, I'm gonna end up with some ratio. The slope could also be something different. For example, like, you know, if I start out with 60%, I could end up with 30% of something, but the line is going to be linear because maybe like, you know, there's some like weird effect that happens and like one type goes one way and the other type goes the other way. The line, if I increase the asymmetry on the catalyst side, I will just only linearly increase the asymmetry on the reactant side, okay? Because these things are working independently. Right. Okay? That is the assumption that Kagan starts to question.
32:37Okay, everyone believed this at the time. Kagan's like, well, you know, if you think about the catalyst itself, we don't actually know how it works, okay? And during a chemical reaction, we've got this metal atom, right, that's like doing a lot of the work, but the metal atom could be doing different things if there are multiple agents involved, okay? Metal atoms normally react and interact with several molecules simultaneously. They're not just like, oh, I'm gonna stick to this guy. They're recruiting all sorts of other stuff. And that's why like metals like zinc and things like that are very important for our body as cofactors because they actually help proteins recruit all sorts of other types of stuff.
33:21Now, here's what he considers, right? Suppose we've got two chiral molecules that are catalysts. There's a left-handed version and a right-handed version, and we combine it with a metal atom, right? Now, this metal atom is gonna recruit two of these to create mixtures. So we're gonna get three possibilities. We're gonna get a right-right mixture, a left-right mixture, and then a left-left mixture, right? But because of combinatorics, if I start out with a certain asymmetry, that asymmetry is only going to grow because of my mixtures. For example, if I start out with 25% and 75%,
34:02I'm gonna end up with 6% and 56%. Like if I start out with 25% left, the combinatorics there is gonna be 0.25 squared, which is gonna be 0.625. So these guys are rounding to... Boo. Yeah, they should say 6.25%, but this is the popular information and they don't wanna deal with decimals, like for the plebes, but it should really be 6.25%. If you guys are taking the GRE, don't round. Don't do that. Okay? So you get 6.25% of the left-hand side. You get something like, I think it's 56.25% or I don't know what the...
34:42You know what I mean? Of the right-right. And then the mixture is gonna be about 38%. It's really 37. something something percent. But that's the key distinction now, right? So you've made these mixtures of molecules that have a different ratio than what you started. It's not that same linear ratio we just talked about previously. Exactly. And now, if you create this type of multi-molecular interaction and you try to run your reaction through, what are the products going to look like? This is the big paper that comes out in 1986 in the Journal of Chemical Society, the Journal of
35:24the American Chemical Society. He shows that actually, for a particular type of reaction of Geroniol, which is depicted on the lower there, we don't get a line. We get a non-linear effect. If I increase the amount of asymmetry or I increase the amount of right-handed versus left-handed, I don't get a straight line. I actually get a difference. I get a slope that is very, very much a non-linear effect. The type of reaction here is the Sharpless Epoxidation. That's named after Barry Sharpless, who won the Nobel Prize in 2001. This is building on some of the asymmetric oxidation stuff that Barry Sharpless had done earlier
36:08on. The left-right catalyst behaves differently, and that is the key distinction that he's trying to make. So, theoretically, what's happening, he actually tries and figures it out. Now we have the complete picture. We've created these left-right catalysts, and we've created the left-left and the right-left. Sorry, left-left and the right-right. Right? What ends up happening is the left-right catalyst, the mixture, can't do anything. It is completely useless. And inert? Yeah, in some sense, yeah. It can't react with anything because, I guess, it's getting confused about which type of reactant to make.
36:50And now, at the very end, you're taking out that middle 38 portion. Yeah, yeah, from before. And you get a huge asymmetry. Yeah yep yep. Before, we had 6%, 38%, 56%. But the 38% is not creating any reactants. And so, if we look at the reactant distribution, we only get 10% of reactants and 90% of the right version. 10% of the left version, 90% of the right version. Which is basically taking up all of the product that would've come out of the left-right because, effectively, it cannot catalyze. There's no catalysis happening. And so, this is non-linear because you're starting with 25%, 75%,
37:37and you're ending up with a 10% and a 90%. And, specifically, this mixing mechanism is a multiplicative thing, right? Which is why we're getting that slope, right? If it was just an additive thing, that the slope would just change, but it would still be a straight line. The fact that it's multiplicative means that I'm getting a parabola, right? And that's why you get a curve in that reaction kinetics. That's the key distinction that's happening. This is the positive non-linear effect. And this is the non-linear part of the Nobel Prize discovery.
38:17Exactly, so if we go back to the top here, right? The official citation is for the discovery non-linear effects and autocatalysis and asymmetric organic synthesis. So now we've identified, this is the first piece. Yeah, the non-linear effects, right? And this is a historic breakthrough. It's historic because many chemists didn't think it was possible. And now they start exploring this new phenomenon. Everyone in chemistry who cares anything about asymmetric catalysis starts exploring this. One of these chemists is Kenso Soai at the Tokyo University of Science. And he comes up with the final link in that Nobel Prize citation.
Nobel PrizeChemistryBiochemistryChemical origin of lifeSynthetic Biology