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August 2, 2006
A Law of the Lab: Yields and Variations
The "Law of the Lab" I alluded to the other day is:
Yields go down faster and more unexpectedly than they go up.
My synthetic organic readers will all know what I'm talking about here. We've all had the experience of running a reaction that we've done many times before, only to find it suddenly giving half the yield that it usually does. One of the most important jobs of a process chemist is to iron things like this out, making sure that they don't happen by either tracking down the variables responsible, or ditching the reaction entirely for something more reliable.
But med-chem types like me don't always have enough time to spend on that sort of thing, so we have a lot of reactions that are in a sort of unstable equilibrium with respect to reproducibility. As long as the different factors involved - purity of the starting material, rate of addition of reagents, efficiency of heating, cooling, and stirring, etc. - are within their (sometimes narrow) green zones, things are OK. But let one or more of them wander off, and the fuses start to blow. All reactions will go to pieces on you if you push such variables too much off their mark, but the difference is that a robust one will stand up to all the variations that you'd usually encounter. A wonky reaction is just one sensitive to something that can be over the line under normal conditions.
And there sure are a lot of them. And the different chemistry that starts happening when things cut loose has a far greater chance of messing things up than it has of improving them. Most organic chemistry reactions are very artificial systems - we're using energetic reagents and conditions to make molecules go down particular paths that they wouldn't do to any useful degree by themselves. There are so many other things they can find to do otherwise, and they'll explore those pathways if they get the chance.
So while it's not completely unknown for a random variation to improve a reaction, it sure is rare. Most of them lead to yet another synthesis of the sticky brown gunk which seems to be a universal thermodynamic sink of organic chemistry. You're threading your way through a swamp of that stuff when you do synthesis, and liable to sink down into it at any moment.
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