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Derek Lowe The 2002 Model

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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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« A Nobel for Ribosome Structure | Main | Hoist, Petard, Etc. »

October 8, 2009

Retire These Reactions!

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Posted by Derek

Here's a question you don't hear discussed very often: are there some synthetic organic chemistry reactions that don't need any more work? I'm moved to ask this because I just came across yet another way that someone has reported to dehydrate an oxime to a nitrile. (No, I won't link to it. You don't need it. No one needs it).

If asked to count the number of times I have seen new reagents that dehydrate oximes to nitriles, I would be at a total loss to even try to guess. But I've seen it over and over and over. Is it possible that we now have enough ways to do this? And that anyone who is contemplating adding another one to the list should instead go do something else?

I'll vote for that. And there are several other transformations that could go on the same list. That doesn't mean that I think that our existing methods for these are all perfect, or that they couldn't be improved. I mean, even for forming amides, I would like an inexpensive reagent that never fails, even with crappy unreactive hindered coupling partners, works at room temperature in about five minutes, and has a ridiculously simple workup. We don't quite have that, do we? But no one's publishing on coupling reagents like that, because they're rather hard to realize. What we get are a bunch of things that are about as useful as what we have already.

And I agree that it's worth having multiple methods to accomplish the same reaction. I've been saved several times by being able to move down the list and find something that works. But how long should the list be? Eight reagents? Ten? Twenty? At what point should something like this cease to become an acceptable field for human effort?

My first nomination, then, for the Retirement Home for Organic Transformations is aldoxime to nitrile. I am willing to face the rest of my chemistry career with only the monstrously long list of reagent systems we have today for that reaction. Further nominations can be made in the comments - I'll assemble a list for another post.

Comments (36) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


1. bored on October 8, 2009 8:07 AM writes...

asymmetric ligands for the addition of diethylzinc to benzaldehyde

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2. processchemist on October 8, 2009 8:12 AM writes...

No more Pd/Cu/etc TMEDA/etc catalyzed Buchwald/Buchwald like aminations/cyanations of aryl halides, thanks, if the new one does not work at 60 °C in 12 hours max. A screen of 12 catalytic systems on your substrate is much faster than reading all the papers on the topic of the last five years.

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3. anon on October 8, 2009 8:34 AM writes...

T3P seems to be a popular reagent here for amide formation, and the workup is pretty straightforward.

see page 11 of the chemfile document.

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4. HelicalZz on October 8, 2009 8:50 AM writes...

Well, so much for that new protecting group I've been working on that comes off pretty much just like many of the others for that same function.



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5. anchor on October 8, 2009 9:01 AM writes...

I have three in my list that I would like to retire and these are....
1. Another condition to demethylation
2. another Metal complex hydride to reduce ketone to alchol and...
3. Modicifications based on PDC/PCC to oxidise alcohol.

Had it enough....

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6. Atticus on October 8, 2009 9:17 AM writes...

How about lengthy syntheses of terpenoids starting from the Wieland-Miescher ketone?

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7. milo on October 8, 2009 9:33 AM writes...

How about all the green methods of BOC protecting an amine/alcohol?

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8. Andy on October 8, 2009 9:43 AM writes...

I disagree that these reactions should be put to bed - for the reasons that you gave above. It may be just the method someone needs, when all others have failed. I agree that people shouldn't be devoting time to searching for them, but if you are doing a reaction with an oxime, and your reagent unexpectedly dehydrates it, then why not just do a little optimisation, test the scope, and if it merits it get a short Synth. Comm. or something out of it. This is the sort of thing that these lesser journals can be useful for.

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9. Slimmy on October 8, 2009 9:44 AM writes...

Formation/cleavage of acetals? Obscure (Lewis)acids for 1000 please!

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10. CMCguy on October 8, 2009 10:13 AM writes...

I am in the "don't be too hasty camp" on this question as although you outline some conditions for ideal reactions that speak to the hearts of process chemists (cheap, reliable, easy work-up, general application, RT and fast) those factors often rarely converge especially when one has to consider yields and impurity profiles. Usually when I see a long list of particular transformations available I take that as a warning that there exists problems with one thing or another with each procedure. Yes it is a pain to have to go through many variants and may not matter so much in medchem where objective is output but in process such can make or break a viable route to large scale (throughput).

All that said I do find it silly that people always first seem to use Diazomethane to make Me Esters when there are so many other means. There are also other reactions where "safety" is not a prime factor that perhaps it should be. Do not recommend Retirements but at least put further these down the "to do" choices.

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11. Curt Fischer on October 8, 2009 10:34 AM writes...

What about engineers doing scale-up? Catalyst cost is probably not a major concern for laboratory research. But would anyone doing aldoxime dehydration ever want to do it at 100,000 liter scales? If so, would catalyst cost be an important issue?

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12. Old Timer on October 8, 2009 11:37 AM writes...

#5 Anchor: I wish there were more demethylation conditions! I once tried to deprotect a mixed acetal that could not planarize, thus was not amenable to standard conditions. I tried 30 or so demethylation conditions and nothing worked. Added another 1 year to a synthesis to go back and replace :(

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13. JAY-Z on October 8, 2009 1:00 PM writes...

1) Conjugate additions to nitrostyrenes
2) Cascade reaction involving 1)
3) Baylis-Hillman reactions
4) Additions of boronic acids to cyclohexenones
5) acetone+p-nitrobenzaldehyde
6) montmorillonite catalyzed ...

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14. TPS reporter on October 8, 2009 3:22 PM writes...

I second the now-commonplace asymmetric diethyl zinc additions to carbonyls. And asymmetric Strecker-type reactions. I don't even open the articles when I see these titles anymore.

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15. mad on October 8, 2009 3:34 PM writes...

Not so fast Derek!

"The greatest obstacle to discovery is not ignorance -- it is the illusion of knowledge."

-DJ Boorstin

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16. nitrosonium on October 8, 2009 3:40 PM writes...

I'd like to reject all "new" procedures describing the oxidation of alcohols to carbonyls. we have them already. all of them. even if you come up with a "new" one, you really haven't.

i'd also like to reject letters or communications which introduce some new and exotic catalyst/reagent that accomplishes a simple organic transformation on a handful of monofunctionalized, uninteresting hydrocarbons. these procedures are invariably not reproducible AT ALL. we are wasting paper with these publications.

if you have something really novel, show that it works on relatively functionally diverse substrates that we care about!!

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17. Danilo on October 8, 2009 3:57 PM writes...

I agree with Andy (#8). Even methods that aren't terribly valuable deserve to see the light of day. This, I think, is why chemists need the equivalent of PLoS One, a journal that doesn't take into account the "significance" of the work. (I know PLoS One is multidisciplinary, but almost no chemistry is published there) As far as I'm concerned, if it's new, and it's scientifically sound, it's publishable. Now that e-journals have become prevalent, there is no good excuse for limiting the literature based on "significance".

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18. AlchemX on October 8, 2009 4:31 PM writes...

Definitely agree with #17. Publish the easy stuff in the e-jouirnals. Good projects for masters and undergrad researchers. I won't ever include it in my RSS feeds though. It'll just be another line in SciFinder/Beilstein searches. These redundant reactions have made my RSS feed of Tet. Lett. the most boring one.

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19. Curt Fischer on October 8, 2009 4:47 PM writes...

My point in #11 being, in case it wasn't clear, that a slightly different catalyst that does the same thing as all the other ones could be cheaper enough to matter at industrial scales.

And if I were a guy doing reaction scale-up, I would be happy to have a bunch of "me too" papers to sort though when looking for my cheapest option.

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20. A on October 8, 2009 5:58 PM writes...

I am surprised that you guys didn't have any problem with Indian winning Nobel! Please stop pointing at a nation if one guy does some cheating some where. There are more jems like Venkat. CEN went on to say that venkatraman was US citizen who was born in INDIA. NO, he was Indian who happened to become a US citizen. If Indian, chineese postdocs and grads quit doing sciences, where would america be in sciences.

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21. bitter pill on October 8, 2009 6:49 PM writes...

my adviser used to say that if there a lot of ways to do a transformation, it's usually because none of them are good.

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22. MidwestProcess Chemist on October 8, 2009 7:33 PM writes...

These boronic acid catalyzed amide formations are pretty promising...kind of nice that the only by-product is water!

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23. Anonymous on October 8, 2009 9:23 PM writes...

AlchemX, #18 "Publish the easy stuff in the e-jouirnals. Good projects for masters and undergrad researchers."

So, what, masters and undergrad people can't do high quality research? There are a lot of reasons why people don't get PhDs, and it is not always about their abilities.

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24. AlchemX on October 8, 2009 10:53 PM writes...


I did undergrad research under masters students, I can say that the easier stuff is much better. Giving an undergrad/MS an alkaloid with five contiguous stereocenters to produce is not a good idea. A masters student practically takes a whole year becoming proficient in lab. I've seen enough masters students drag out their MS in synthesis for 3-4 yrs. It's just not economical. Do something simpler. Their ability may be higher than that, but there is not enough time for it to show. Besides, they could be making some real money in the mean time. No offense to them, but if they want to dig deep, just go PhD. See you in seven years and hope you can get a job.

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25. aa on October 8, 2009 11:30 PM writes...

@ #22- these reactions have been significantly improved by Dennis Hall at Alberta- the trick is to use ortho-iodophenyl boronic acid

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26. Handles on October 9, 2009 1:52 AM writes...

@ #22 I remember reading in OPRD that boric acid itself works for amide formation, cheap for scale-up and the catalyst filters off. Cant find the ref now but OrgSyn has more on the subject.

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27. Jose on October 9, 2009 2:31 AM writes...

"the trick is to use ortho-iodophenyl boronic acid"

Ahhhh, doesn't this negate all the nifty advantages of boric acid? At that point you might as well just use EDCI or HATU and be done.

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28. CT Chemist on October 9, 2009 10:05 AM writes...

CMCguy and bitter pill:
Lowe's Laws of the Lab #7: When there are twenty ways in the literature of running a reaction, it means that there is no good way.

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29. CMCguy on October 9, 2009 10:50 AM writes...

CT Chemist I agree with sentiment however this may be a corollary or adjunct warning as Derek's Post implies to me at least Law #7 would be something like: "If there are already good reactions/transformations available don't bother using or inventing new ones". Regardless would be nice to see additional such threads.

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30. aa on October 9, 2009 6:40 PM writes...

@jose #27- oops sorry, forgot to mention the reaction is catalytic. see Angewandte Chemie Int Ed. 2008, 47, 2876-2879

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31. midwest process chemist on October 9, 2009 7:08 PM writes...

Actually, along the "less waste front", it would be nice to see methodology developed to do direct displacements on alcohols instead of having to convert to a sulfonic ester or halogen. I'm only aware of one paper out there (OPR&D from about a year ago). Anyone else know of someone doing research in this field?

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32. milkshake on October 9, 2009 7:13 PM writes...

@31: there are reasonable Ru and Ir catalysts for direct amination of alcohols with amines, in solvents like toluene - it works by redox mechanism though so the nucleophile has to be an amine

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33. Midwest Process Chemist on October 9, 2009 8:38 PM writes...

Thanks, Milkshake. I should have been more specific. What I'm real interested in is displacement via an Sn2 mechanism so if you start with a chiral alcohol, you get a chiral product.

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34. milkshake on October 10, 2009 4:42 PM writes...

I have seen in situ activation/allylation protocols with allylic alcohols promoted by borate esters and catalyzed with Pd(0).

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35. Foger on October 11, 2009 3:24 PM writes...

I would submit that 99% of "organocat" reactions fall in this category.

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36. Norepi on October 24, 2009 8:42 AM writes...

@ #28: This reminds me of an old Amos Smith joke.

Q. Why are there 35 ways to cleave a dithiane?
A. Because none of them work!

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