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November 5, 2012
Caring About Yields?
The discussion here last week about exaggerated reaction yields has gotten me thinking. I actually seem to go for long periods without ever calculating (or caring much) about the yields of my reactions.
That's largely because of the sort of medicinal chemistry work that I do - very early stage stuff, about as far back as you can get. For that work, I like to say that there are really only two yields: enough, and not enough. And if you can get product into a vial, or intermediate sufficient to make more needed analogs, then you have enough. I'd prefer that reactions work well, of course, but "well" is defined in my mind as much (or more) by how clean the product is than how much of it gets produced. A lower-yielding reaction whose product falls out ready to use seems nicer than a higher-yielding one that needs careful chromatography to get the red stuff out of it.
That's the opposite of the way I used to think when I was doing my grad school work, of course. Twenty-seven steps in a row will get you thinking very hard indeed about yields, especially later on in the synthesis. It occurs to you pretty quickly that if you take a 50% yield on something that took you two months to make, that you're pouring a month's effort into the red waste can. If you're going to take a nasty yield in a long sequence, it's much better to get it over with in step one. You'll see this effect at work in papers that just start off from a literature reference intermediate (the "readily available compound 3" syndrome), which can mean that compound 3 is a nasty prep which would besmirch the rest of the sequence were it included.
I'd certainly think differently were I in process chemistry, too, of course. And when I have to work downstream on a project, I do spare a thought for the ease of the chemistry, because that's closer to the point where my optimization colleagues will have to deal with what we produce. But back at the early stage, I have to admit, I really don't care all that much. The vast majority of the compounds that get made back there are not going to go anywhere, so whatever gets them made and tested quickly is a good thing. The elegant synthesis is the one that gets it out of the lab and down the hall, whatever the yield might be.
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