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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 7, 2004

Take it Off!

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Posted by Derek

When I was an undergraduate, learning all the chemical reactions that you have to learn in undergraduate courses, I got a few wrong ideas into my head. Well, probably more than a few, but you know what I mean.

One of them came from Theodora Greene's book on protecting group chemistry, which was a new item in its first edition around the time I was doing my first summer research project. This was, and remains, the best single source for finding out how to attach and remove groups that will protect reactive parts of your molecule until they're ready to be unveiled. Organic chemists spend a fair amount of time using these, especially for things like amines and hydroxyl groups, which are liable to become personally involved in all sorts of reactions if they're not restrained.

In my first encounters with these, I got the (completely mistaken) impression that all protecting groups tended to have specific recipes, precisely targeted for their removal. Methoxymethyl ether group to take off? Reach for the zinc bromide! Pivaloyl ester? Methyllithium! And so on. There was page after page of this sort of thing.

And it's not like those are poor choices, to be sure. I've used that methyllithium one myself, although not since about 1988. But zinc bromide isn't called for because of its essential zinc bromidey properties, it's called for because it's a Lewis acid, and just about any Lewis acid will take off a MOM group. Some will be faster than others, some might do things to the rest of your molecule which others wouldn't, but they'll all get around to cleaving your methoxymethyl ether. As will good old protic acids - aqueous hydrochloric will take one off just like it was 1895 again, if the rest of your molecule can stand it.

Learning all this, which I did in my later undergraduate years, was a good way to start appreciating the mechanistic side of organic chemistry. There really aren't that many reactions, no matter what poor sophomores think while they memorize page after page of them. Organic chemistry isn't zoology. And it also hit me, after a while in graduate school, that the claim of a new, mild, wonderful way to remove a given protecting group was a pretty good method to get a paper published, which might - just might - have something to do with their proliferation.

Comments (3) + TrackBacks (0) | Category: The Scientific Literature


1. The Novice Chemist on November 8, 2004 9:32 AM writes...

There's another good way to learn protecting group chemistry: when your protecting group falls off when you didn't want it to.

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2. Derek Lowe on November 8, 2004 2:13 PM writes...

Oh, yes. For example, the best way I've found to take off a trityl group is to depend on it. Trust in it, base your whole synthesis around it, and it'll fall off with an audible clang. . .

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3. Dawn B. on November 8, 2004 7:34 PM writes...

Yah. I love protecting groups, but understanding all the on/off stuff was interesting until I hit that light bulb you reference.

The line about sophomore chemists: I always feel that bio majors make it harder on themselves by memorizing. If you just understand the WHY behind a given reaction, you don't have to memorize what happens when a carboxylic acid meets up with an amine.

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