Who I'm Reading Today

https://www.science.org/content/blog-post/fixing-reaction

Some chemistry today, drawn from real life (mine, anyway). I was setting up a short series of palladium-catalyzed couplings the other day (Buchwald-Hartwig type, C-N bond formation), and since there were very close precedents to my structures in the chemical literature, I naturally just borrowed the known conditions. There was nothing out of the ordinary about them; it seemed as if they’d work about as well on my starting aryl bromides as it did on the ones already described.

Well, they didn’t, of course. Which is the way of such metal-catalyzed couplings, which is why there are fifty gazillion ways of running them in the literature. They work until they don't! You can vary the catalyst ligands, first off, and boy are there are lot of them out there. You can change up the solvent, and the base needed for the reactions to go. There are other additives to try, and you can even vary the source of the palladium. (These days, if you know the system well enough and have some money to spend, you can order “pre-cat” materials where the ligand/Pd complex is already formed for you). In fact, here’s a recent Organic Process Research and Development paper that investigates that last variable in great detail: some catalyst systems don’t seem to care where their palladium comes from, while others care very much indeed, in case you were wondering.

But I had no desire to wander off and try a whole list of reaction conditions. In the manner of discovery biopharma chemists everywhere, I didn’t want to perfect my reaction - I just wanted it to make a reasonable amount of product so I could get on to the important stuff! I was staring at my compounds and trying to think about what made them different from the known examples, and the main thing was that I had an extra functional group at the other end of the molecule. I hadn’t thought it would be a problem, but I wondered if it was perhaps sensitive to the base I was using (which was good ol’ cesium carbonate). So I was very interested indeed when I saw this new JACS paper from the Hartwig group themselves.

It goes into great detail about the use of a base that I’d heard of but never actually tried, potassium 2-ethylhexanoate (K-2-EH). That might be an obscure-sounding reagent (along with the starting 2-ethylhexanoic acid) unless you’re a Real Industrial Chemist. Those compounds show up in a lot of polymer, coating, formulation, and materials science applications, and the acid is one of the largest-scale compounds of its kind produced industrially. So you can buy big ol’ bottles of the sodium and potassium salts relatively cheaply, and the potassium one is especially notable for dissolving in all kinds of organic solvents (where a lot of other potassium salts and carboxylates may not).

The Hartwig group found that it’s an excellent choice in the C-N couplings that bear the name, partly because of that solubility and partly because it’s a much milder base than many that people reach for. I read up on that, checked our inventory, and found a bottle of the stuff one floor below me. A milder base was about the only idea that I had to fix my problem, so it seemed like a good opportunity to try it out.

And by golly, I checked this morning and the reaction is making beautifully clean product, as opposed to the mixture of dark gunk I got with the cesium carbonate conditions. It is relatively rare that we get to actually figure out what’s going wrong with our reactions (unless you’re a process chemist, in which case that is your entire job!) But it’s also rare to fix things cleanly on the first shot - I can count the number of times I’ve been able to turn things around like this with one change on the fingers of my hands. Maybe just one hand, and that’s after forty years at the bench. 

That’s not as grim as it sounds, because remember, over most of that span I’ve been in the world where (as I like to say) there are two yields for reactions: Enough and Not Enough. Most of the time, even a relatively crappy conversion, the sort of thing a process chemist would not put up with for ten seconds, has been Enough, and I move on. But when all your starting material turns to gorp, you don’t have that option. Honestly, I would have settled just for a better product/gorp ratio, but what I got was the cleanest coupling reaction I’ve run in a long time. So thanks to Hartwig and collaborators, and those of you troubleshooting Pd reactions, try a K-2-EH run and see if it helps! 

Now I can move on (after another step or two) to the real reason I'm making these compounds, which is to do something very odd to an unsuspecting protein, and sadly I can't talk about that. But without making the needed compounds, you can't test out those weirdo ideas, can you? I'm glad these are now unsnarled.

https://www.science.org/content/blog-post/fixing-reaction