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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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January 17, 2006

Gimme That Old Time Reaction

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Posted by Derek

Many of my readers are professional chemists, but many aren't. For those who've only had sophomore organic (or less), it sometimes comes as a surprise to find out that we actually use a lot of those reactions that you have to learn.

That's a strange thing about chemistry as compared to most of the other hard sciences. I don't think that much that you learn in a second-year physics class comes up in the day-to-day life of a physicist, and the same goes (and how) for most biologists. But I'm here to tell you: we professional organic chemists really do Fischer esterification, the Knoevenagel condensation, and a lot of those other ancient reactions. Not just once in a while, either - we do 'em every day of the week. My lab, for example, has been wrestling the last few days with forming and using a particular Grignard reagent, and Grignards have been a standard part of undergraduate labs for generations.

Why do we stick with these moldy reactions? Because they work, for one thing. Reducing an aldehyde with sodium borohydride, for example, is a procedure that's been around for a good forty years. But it's a mighty rare aldehyde that won't reduce cleanly with the stuff. It's fast, it's cheap, and it's generally easy to clean up the reaction, so why not?

Another reason is that these reactions are close to the fundamental principles of organic chemistry. If you're going to make an ether from an alcohol, for example, it's hard to see how that's going to happen without an oxygen attacking a carbon center somewhere along the line. I mean, you're forming an oxygen-carbon bond, so you can't avoid it. And oxygen is so electronegative, you have to figure that it's going to have some sort of negative charge built up on it, so it's going to be attacking something with a partial positive charge. . .and there's the good ol' Williamson ether synthesis, the classic nucleophilic substitution. To have a completely different ether synthesis, you'd almost have to have a completely different form of oxygen.

And that brings me to an observation that I've made before - that you can be a fine medicinal chemist using nothing but reactions from a sophomore organic textbook. It's a bit humbling to realize that, because catching on to that fact tells you where chemistry stands in drug discovery: not as an end in itself, but as a means to an end. And if those means turn out to be reactions that an eighty-year-old grandmother could learn to run, and that are older than she is on top of it, well, fine. We're not here to use the latest hot reaction, unless it can speed up making a drug. Because that's the point.

Comments (13) + TrackBacks (0) | Category: Life in the Drug Labs


1. larry on January 18, 2006 12:23 AM writes...

On forming ethers, one nice way is to do an acid catalyzed reduction of a ketal. It's a key step in the Tamiflu synthesis route and fundamentally different from a Williamson synthesis.

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2. UndergradChemist on January 18, 2006 12:36 AM writes...

In the lab I work in, all the synthetic targets are delicate enough that many of the older reactions are too harsh for the functional groups involved. I've rarely seen anyone, for example, reflux something overnight, or dump HCl into a reaction. I suppose that's less of an issue in medicinal chemistry, considering the contraints on the types of molecules that need to be generated.

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3. Petros on January 18, 2006 2:51 AM writes...

And don't forget that even if the med chem labs develop syntheses using new reactions and exotic reagents, that if the synthesis goes to process development people, it is rare for them to want to consider the use of such reagents. THey want reliable(old) chemistry that is safe to use on a large scale, e.g. borohydride reductions.

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4. Grubbs the cat on January 18, 2006 7:09 AM writes...

I don't want to take anything away from the folks who think that everything important used to be discovered more than 40 years ago. But think about the opposite of the aldehyde reduction (maybe a better example, because chemists much more likely generate aldehydes than reduce them): what did you use before TPAP, Swern, TEMPO, IBX were around? Probably mostly Cr(VI) reagents (brrrr...), maybe MnO2 for the benzylic cases. I really think that in this case I'd much rather do chemistry now than 50 years ago.
(But of course I appreciate that a lot of the good old stuff is great and will never die.)

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5. Derek Lowe on January 18, 2006 8:45 AM writes...

That's true, Grubbs - in fact, I did a post here last year about how no one uses PCC any more. (And having had to make fresh batches of MnO2 twenty years ago, I have no desire to see it make a big comeback, either!

So there are areas that have evolved. The Grignard reaction, though, will be with us for a long time yet. . .

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6. RKN on January 18, 2006 9:13 AM writes...

If I recall correctly Grignard reagents can be used to synthesize a carboxylic acid, which involves forming a C-C bond. I can still remember my organic prof becoming frenzied when he revealed this during lecture, yet most in the class were unmoved, "Yea, so what?"

Professor: "So what?!!" We're making a CARBON-CARBON bond here folks -- this is not an easy thing to do!

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7. Tom McEntee on January 18, 2006 10:05 AM writes...

Kolbe-Schmitt and Grignard reactions are great for producing carboxylic acids in substantial volume. In the 1970-1980s, we routinely ran both in 2000-4000 gallon reactors at Arapahoe Chemicals (then Syntex, now Hoffmann-La Roche) in Boulder, CO. In general, these ran without incident although we once blew a rupture disk on a 2000-gal reactor filled with a pressurized mixture of a substituted naphthol, THF, NaOH, and CO2...and then watched the spray arc onto the plant crew's cars in the parking lot...we lost the batch but they all got new paint jobs. For years, dl-naproxen was manufactured using a Grignard reaction developed in Boulder. Kirk-Othmer has a good description of the Grignard reaction--I wrote this chapter for the K-O edition that was in the rolling publication cycle during the late 1970s.

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8. Milo on January 18, 2006 11:43 AM writes...

Here are two questions this post raises for me:

1) Is it possible that the field of organic (synthetic) chemistry is coming to the point where it will transition to an "applied" science rather than a more "basic" one? There are clearly things we want to learn, but as a whole, are we close to "filling the tool box?"

2) Do the synthetic folks here have a favorite reaction? I myself like the Claisen Condensation.

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9. Tom McEntee on January 18, 2006 12:28 PM writes...

Milo -- If you looked at the volume, say, metric tons, of organics produced with good old standard techniques as your meter stick vs. metric tons of organics produced using synthetic methods described in JACS in the past 5 years, you'd come to the conclusion that synthetic (organic) chemistry is definitely in the "applied" category. While there have been some stunning advances in catalysts and carbon-based nanostructures, much of we collectively do is applied research. I include variations on name reactions in this category. Quick! who remembers the Cristol-Firth modification of the Hunsdiecker reaction?

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10. tom bartlett on January 18, 2006 1:17 PM writes...

"1) Is it possible that the field of organic (synthetic) chemistry is coming to the point where it will transition to an "applied" science rather than a more "basic" one?"

Perhaps. But Med Chem is a pure scinece that uses many "old" tools.

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11. Mark McPhee on January 18, 2006 2:35 PM writes...

I myself am fond of the Ramberg-Backlund reaction.

(Or any Cu (I)-catalyzed C-C bond reaction using a Grignard for that matter)

Then again, you are nearly guaranteed a stress-free day in the lab if your goal is to complete a Finkelstein reaction (at any scale).

Did I ever meet a chemical reaction I didnt like? Sure, Swern and anything run in straight pyridine

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12. LNT on January 18, 2006 4:19 PM writes...

Derek, while I can see where you are coming from, I think you are really discrediting advances made in synthetic chemistry over the last 10-20 years. Here's some examples of "modern" synthetic chemistry that was never covered in my sophomore organic class (~11 years ago now):

1.) Palladium couplings -- this has become a mainstay of C-C bond formation in every medchem project that I've been a part of. Suzuki and Heck rxns in particular.
2.) Buchwald aminations -- again proved very useful in a couple of projects. Wasn't covered 10 years ago. (was barely around 10 years ago)
3.) 3+2 dipolar cycloadditions -- great way of making various heterocyles. Only 4+2 (Diels-Alder) is generally covered on an undergrad level.
4.) Ring closing metathesis -- it seems obscure -- but I've used it multiple times to make "unique" ring systems.

Sure you can do a Fischer Esterification -- but what about TMS-diazomethane to make methyl esters with essentially no workup and no side products? Not covered in my undergrad textbook. "Modern" synthetic chemistry is often aimed at more efficient and/or more selective ways of doing classical transformations. The impact of this should not be understated -- I can make molecules MUCH more efficiently using synthetic methodology developed over the past 10-15 years than I could by using only the "tried and true" methods.

Classical reactions are wonderful -- but if you want to get into "novel" chemical territory efficiently, you had better keep up with modern syntheic literature.

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13. Derek Lowe on January 18, 2006 4:46 PM writes...

I'll do a follow-up post to address that very point!

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