I’ve been an organic chemist for decades now, but I have somehow never had the need to run an ozonolysis reaction. It’s a specialized operation, but it does a transformation that’s otherwise not easy to effect: oxidatively splitting an alkene into two separate aldehydes. You need an ozonator, which is generally a rather bulky electric device that someone in the department bought a long time ago, and you generally have to go around asking “Does anyone know where the ozonator is?” It’s that kind of equipment. Ozone itself is not a stable substance; you have to make it fresh, and an ozonator does that by passing oxygen gas through an electric discharge. That’s how most people encounter it in the wild, during thunderstorms, where it’s produced by lightning strikes. Toxic, reactive, and explosive if concentrated – ozone has a lot going for it, and the intermediates formed during ozonolysis are most definitely hazardous. The primary ozonides feature three oxygen atoms in a row single-bonded to each other after the ozone adds to the alkene, and there is just no way that those things are not going to blow up if you give them a chance.
The key is not to give them a chance. Ozone reactions are always run dilute, and you never, ever concentrate the primary ozonides. You can see that the reaction is running, because ozone (weirdly) is colored bright blue, and when the blue color persists in the chilled flask it’s generally the signal that you have ozonated whatever in there could be ozonated. The primary ozonides rearrange to secondary ozonides, which are better but still hazardous, because they still feature endoperoxide groups which are also the sort of thing that we very much try to avoid. So you destroy those during the reaction workup to give you the aldehyde products.
As you would imagine, no one is eager to scale this sort of reaction up. There are several flow-chemistry methods to get that to work, and that’s absolutely where I would turn if I were forced by malevolent space aliens to run these reactions on scale. But a giant batch ozonolysis is just not on the table, because it could soon be all over the walls, assuming that any walls are left. So this new paper could be of interest: it presents a photochemical alternative to ozonolysis that gives you exactly the same products from the same sorts of starting materials, and also holds out the promise of doing the reaction selectively if you have more than one alkene to worry about.
It involves addition of a nitro group (from a nitroarene) to the alkene, producing (after some single-electron rearrangements) an odd-looking five-membered 1,3,2-dioxazolidine. Now, ozone immediate does the dipolar cycloaddition reaction with alkenes even in the cold, but nitro groups (despite having superficially similar “oxygen-plus” and “oxygen-minus” ends) just don’t under thermal conditions – it makes thermodynamic sense if you look at the starting materials and the products, but the kinetic barriers in the mechanism are just too high. But many thermally unlikely reactions find a way under photochemical conditions, and that’s what happens here. As the paper describes, reactions like this had been reported, but even those weren’t too easy to realize. The key is to make the aryl ring very electron-poor, as revealed by a good ol’ Hammet plot (classic physical organic chemistry comes through again!)
The dioxazolidine intermediates seem to be perfectly thermally stable, and I actually prefer calling the intermediates by that name as opposed to “N-doped ozonides” as the paper does, because I worry that that name will set off unwarranted fears by using the O-word. They are decomposed by water to give the aldehyde products, though, as revealed by isotopically labeled water experiments, and there are additives like urea to suppress side reactions. There’s a good range of substrates illustrated for the reaction, with some useful tweaking along the way (such as using a mixture of hexafluoroisopropanol and dichloromethane as solvent in some cases. And as mentioned above, varying the electron-withdrawing groups on the nitroalkene reagent can provide some really useful selectivity if your substrate molecule has more than one alkene, which is something you’re rarely (if ever) going to see with straight ozone.
So this looks quite useful, although (paradoxically) it may well find more use on small scale with parallel high-throughput reactions. Ozonators are pretty lousy at that kind of setup, too, as you’d imagine, but setting up multiple photochemistry reactions in a reaction plate is no problem. As for larger reactions, photochemistry on scale is something you didn’t use to see much, but in recent years it’s had a lot of engineering experise thrown at it, so that will help. You’ll have to deal with the production of the aryl hydroxylamine from the nitroarene, though, which is where that reagent ends up, and that waste stream might well be a problem. One thing you can say for the classic ozone reaction is that it’s pretty atom-efficient, although you do need some sort of reducing agent in the workup. But overall, I think this will be a really useful addition to the organic synthesis, and it does indeed have the potential to make the ozonator machines even dustier and harder to find than they already are. . .
