Today’s post is one for my fellow organic chemists to wonder over. This new paper from a group at the University of Bari describes a palladium-catalyzed coupling reaction of alkyllithiums and aryl halides. And that in itself is not that remarkable – it’s not easy to get that combination to go, not least because you might end up with an alkyl halide and an aryllithium instead, but (as the paper itself takes care to note, the Feringa group has published a series of reactions in this category.
What makes this one unusual is the way the reaction is run: you take your aryl halide and palladium bis(tributylphosphine) catalyst and stir them in water with sodium chloride added. Then you run the speed up to a vigorous vortex, in the open air, and quickly add a solution of the alkyllithium in a nonpolar solvent (such as cyclohexane). In about 20 seconds you’re done, coupling in up to 98% yield. Yes, you’re adding an alkyllithium to water, and what’s more, you want to be sure to do it in the open air (deoxygenating the system lowers the yields). You need the chloride salt additive, too.
Now that’s a surprise. Most organic chemists picture the quenching of a reactive reagent like an organolithium as pretty much a diffusion-controlled process – the first water atom it sees gets reacted with. But apparently you can get this coupling to go, in water, but get it to go in a Pd-catalyzed manner, which means that some of those organolithiums are having to wait their turn to react. The main way I can picture this happening is inside small droplets of the organic solvent. The relative concentrations of the reactants must be pretty high inside those and there’s a high surface area to aid in diffusion – you certainly can’t rule out some effect at the solvent interfaces as well, and if the droplets are small enough, they’re basically all interface. Meanwhile, the oxygen present is helping in some sort of oxidation process to keep an active catalyst, and the chloride is having an effect on the active catalyst structure as well (a phenomenon that’s been noted in more conventional reactions).
But it’s not a reaction that I would have thought to try! If you switch to methanol, all you get is dehalogenation of the aryl compound. If you try other Pd catalysts, the whole conversion breaks down. Secondary organolithiums work, as do heteroaryl halides. So if you’ve got a quick substitution to do and you have the lithium reagent on hand, give it a try – and come back here to the comments to tell everyone how it worked (!)