Since I was talking the other day about getting published procedures to work (or not!), I thought I should mention that most chemists have, at one time or another, had reactions of their own that not even they can get to work right every time. Most chemical reactions are reasonably robust, within limits (see here for a proposal to establish some!) But every so often, you come across one that has a narrow tolerance, sometimes for things that you can’t even put your finger on.
I’ve seen this happen particularly in low-temperature carbanion reactions. Some of these anions don’t particularly want to form in the first place, and they can be quite sensitive to concentration, the presence of different amounts of salts and counterions, variations in temperature, and so on. The rates and efficiencies of cooling and stirring can affect some of these factors, as can the age and handling of the reagents, and the rates at which they’re added into the reaction mixture. If you’ve got a system that just barely works, a lot of things can push it over the edge.
My personal experience with this first came in grad school, when I had a cyanocuprate reagent opening an epoxide. As I mentioned on the blog a few years ago, I tried that system out, after several other reagents had given not-so-great yields, and it worked really well. So I tried it again – same results! I scaled it up (at the time, “scaled it up” meant running it on about a gram), and it worked again. Problem solved! Little did I realize that the reaction would never work again. It failed the next time, and the next, and the next. I tried everything I could think of. I made everything cleaner, I made everything fresh: no product. I made everything sloppy, with no particular care, the way I’d done it in the beginning. No product. Nothing ever worked. I never did sort out what was going wrong; it was easier, in the end, to find another reaction.
Scaling up such a reaction is especially difficult – even relatively laid-back reactions have to be looked at closely when moved up to larger scales, much less a jumpy, skittish one that gets the vapours and passes out at the first sign of trouble. It’s the job of the process chemists to avoid such narrow-window chemistry whenever possible. The idea process reaction is one that provides the same yield, with the same purity profile, under a wide range of conditions: foolproof, in other words. Naturally, nothing is really foolproof (fools are too tricky), but you do what you can.