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October 4, 2007
No Problem At All
I was listening to a seminar speaker today, who as an aside mentioned forming an ester as “about the easiest reaction that you can do”. He had a point. If you have a free carboxylic acid, combining it with an alcohol and some acid will generally give you some amount of the ester, and most of the time it’s a high-yielding reaction. But there are problems if the acid is next to a chiral center, or if there are other functional groups that don’t like being cooked with acid catalyst. So while this one is easy, I’m not ready to give it the title. (The speaker had had trouble with it himself).
But if it’s not the winner, what is? Displacement of a leaving group with a powerful nucleophile (fluoride, azide, cyanide) is usually pretty foolproof, but we’ve all dealt with structures that are too hindered to do it well (or decide to eliminate and form an alkene instead when forced). Reduction of an aldehyde to an alcohol is also hard to mess us – good old sodium borohydride – but chiral centers next to aldehydes are untrustworthy in the extreme. You may get your alcohol, only to find that the dying aldehyde left you a scrambled stereocenter in its will.
How about forming an oxime from the aldehyde instead? I haven’t had to do that nearly as much as the other reactions mentioned, but every time it seemed like (as an old labmate of mine put it) “a reaction that my grandmother could do”. And if you want to cheat a bit, and start from a really reactive system, then it’s hard to beat formation of an amide from an acid chloride, which is why you see so many amides. But my pick for a reaction that can’t fail is another one from the leg-up category: the formation of a urea from an isocyanate. It has to be an awfully hindered or non-nucleophilic amine for that not to work, or a really weird isocyanate. Anyone have an easier reaction than that?
The problem with talking about these things, though, is that when they fail you, you feel like a complete dodo. I once had a primary alcohol that I just could not put a TBDMS protecting group on, and I still remember the looks of pity in the eyes of my co-workers when I would complain about it. When something like that turns on you, you find yourself wondering if maybe you should have gone to truck-driving school instead, like Mom always wanted.
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