jack

https://www.science.org/content/blog-post/reaction-stirring-part-two

Some weeks back I wrote about a paper suggesting that for many organic chemistry reactions stirring is not very necessary. That one sure set off a lot of comments (here on the blog, on social media, in my own email and conversations, etc.)! I wanted to revisit the topic in light of two more publications since then.

First off is this preprint, a swift response to the original, from a group of industrial chemists. They do a good job of reviewing the principles behind reaction mixing, and they emphasize that larger-scale reactions are going to be much more sensitive to its effects. I don’t see how anyone who’s done scale-up can disagree! I do have to note that the first paper did most cover smaller-scale reactions and that the authors did note that fact. The response paper is written by people who think about larger-scale reproducibility all the time, and under those conditions I don’t think anyone can argue about taking another variable out of the system by using reproducible stirring and mixing protocols. There are too many considerations of mass transfer, concentration changes, temperature gradients and more to ignore.

But on a small scale, how much do these matter? I think that’s what the first paper was getting at. So this new analysis of that paper’s actual data is certainly worth a look. The author takes the extensive supplementary data from that paper and goes back over it statistically, coming to somewhat different conclusions:

. . .where the lowest-yielding reaction group shows the largest overall increase in isolated yield (4.5%; 95% CI: 2.6 to 6.4%; p < 0.0001) with stirring. Stirring of moderate yield reactions is associated with a 1.6% (95% CI: 0.4 to 2.9%; p = 0.0082) increase in yield, while the highest yielding reactions show smaller effect sizes in stirred versus unstirred reactions (0.8% increase; 95% CI: 0.4 to 1.3%; p< 0.0001). These results suggest that while the overall change in yields with stirring in these data for many reactions are modest, there is extensive variation of impact, and stirring is associated with real and practically important increases in isolated yields across a wide range of substrates and reaction manifolds.

So (at least on a certain scale) reactions that work well are going to work well whether you pay attention to stirring them or not. But in other cases, it seems that you can get a slight (or sometimes more than slight) edge by stirring. I’d be willing to bet that these yield increases are well below what a random set of bench chemists would have assumed, though, so in one sense the original point stands (so long as it’s “stirring isn’t as important as you thought” rather than “stirring isn’t important at all”). And for larger scale reactions, I think that “stirring is important” is still undisputed (at least it had better be in any lab I’m working near!) 

And the reproducibility angle is a good one to remember as well. I do mostly exploratory reactions on small scale, so I really will never notice if my yields vary between 72% and 78%. But a process chemist will notice that for sure (and will also be working hard to find a way to not run such crappy reactions to start with!) I’m in the world (as I’ve said before) where there are basically two yields for a reaction, “enough” and “not enough”, and as long as I’m over the threshold and can move on I’m probably happy. But that is certainly not everyone’s world!

Looking over the re-analysis of the reaction yields, it seems that the reaction types that showed the biggest pro-mixing effects were metal-catalyzed cross-couplings, electrochemical reactions, polar mechanisms with a lot of anion/cation character, and (weirdly, to me) rearrangements like the Claisen and Schmidt. The first two categories I can well believe, but the last one strikes me as odd because the Claisen (and many other sigmatropic rearrangements) are unimolecular, and you wouldn’t expect big mixing effects. The Schmidt is different, since you’re having to form an acyl azide (through a polar mechanism, a reaction class already noted) before the expulsion of nitrogen, and even after that you have to have water adding in, etc. So I can imagine mixing effects on that one, but the Claisen is a harder sell for me, unless the starting diene is having to form in situ prior to rearranging. Perhaps that’s what people are seeing with things like the Eschenmoser or Johnson variations of it? Those have more polar-leaving-group mechanisms tacked on the front end of the process, which could fit.

So that’s the current state of debate, but I am willing to be that we haven’t heard the last of this topic. I’m interested in seeing where this all goes, but I would advise people to watch closely for signs of people talking past each other, in the “Elephants are big!” “No they’re not, they’re gray!” fashion. It'll be easy for that to happen. I’ll report back as things develop!

https://www.science.org/content/blog-post/reaction-stirring-part-two