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March 23, 2006
Crystals of Doubt
Here's a limits-to-knowledge post for you. On Wednesday, when I was cranking out a batch of an intermediate we're using these days, I needed to separate two fairly closely related compounds (which I'll call A and B) from each other. One surefire way to have done that was chromatography, but I just didn't have time for that. While I was rota-vapping down the mixture, I noticed that some white crystals were starting to come out of the methylene chloride solution, so I took the flask off and checked a small sample of the solid. Sure enough, it was pretty pure A, so I filtered that off and continued.
Taking out all the solvent left me with more white stuff, which was mostly B, with some A still hanging in there. In the past, we'd purified B by crystallizing it from another solvent mixture (ethyl acetate/hexane, the first combination the lazy - or just plain experienced - organic chemist reaches for). So I tried that out, dissoving the solid in a small-to medium amount of hot ethyl acetate, then adding hexane while it was still warm. I cooled the solution down by dipping the flask in ice water until it had come down to about room temperature, and was swirling it around when suddenly it starting snowing white powder. Ta-daa! A check of this stuff showed that it was almost completely pure B. The solution, for its part, was now a majority of A with some B left around. I took what I had and ran with it - this was one of the bird-in-the-hand situations, because people were waiting on this stuff.
My point is that such things are almost completely empirical. I've never heard of anyone who could predict from first principles what solvent system to use to get something to crystallize. I'd be tremendously impressed if anyone could take the structures of my two compounds, feed them into a dissolvo-matic program and announce "Yep, methylene chloride for A, and ethyl acetate-hexane for B. That'll do the trick."
As far as I know, there's no such thing, and no one is even close. I'd be glad to hear if I'm wrong. But if we can't predict, even just in rank order, what solvents will dissolve (or crash out) a given molecule, just how good is our molecular modeling, anyway?
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