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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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« A Quick Tour Through Drug Development Reality | Main | Shootmenowicene »

August 15, 2012

More On Reproducing Scientific Results: Organic Chemistry Edition

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Posted by Derek

Yesterday's post on reproducing scientific results got me to thinking about the application of this to organic chemistry. How much of this are we going to see, compared to biology?

Not as much, is my guess. Some of the barriers to reproducibility are too low to bother with, while others are too high. In the "too low" category are many new synthetic method papers. People try these things out, if they look useful at all, and they either work or they don't. Most of the time, you end up finding the limits of the reported method - your substrate failed dismally, but when you look, you realize that you had a basic tertiary amine in your molecule, and none of the examples in the paper have one. Ah-hah.

It's rare that a useful-looking reaction turns out to be completely non-reproducible across multiple structures (although it has happened). Here's a paper from 2000, by one Vincent C. O. Njar, claiming that carbonyl diimidazole reacted with hydroxy groups to give direct N-alkylation of imidazole. Two years later, Walter Fischer from Ciba Specialty Chemicals took this paper apart in detail, showing that it did not work and could not have worked. The products were carbamates instead - not surprising - and the original author should have realized this (as should the referees of the paper).

Then you have total synthesis. And here, the barrier is too high: no one is going to reproduce these things after a certain point. A 48-step synthesis of Shootmenowicene could appear tomorrow, and the odds are overwhelming that no one will ever explore its heights again. There have been total syntheses that have been received with grave doubts (hexacyclinol!), but no one, to the best of my knowledge, has gone back over every step of one of these. The return on the investment of time and money is just too low - which, to be frank, is a sentence that sums up my opinion of a lot of total synthesis work these days.

Where the Reproducibility Initiative could come in handy inside organic chemistry, though, would be for unusual things of wide applicability that are still hard to believe. The famous "NMR chirality" scandal at the University of Bonn in the 1990s would be a good example of this. This was a startling result - that the chirality of organic reactions could be measurably influenced by the handedness of an applied magnetic field - and many people had trouble believing it on physical grounds. They were right, too, because it all turned out to be faked by an individual inside the group, a fact that was only discovered after much effort and embarrassment. Having immediate access to third-party reproducibility testing would have sped things up quite a bit - and perhaps if that access is more widely known, used, and appreciated, we might see fewer bizarre cases like this in general.

Comments (16) + TrackBacks (0) | Category: The Scientific Literature


1. CanChem on August 15, 2012 3:13 PM writes...

As I was still in high school when both those Synthesis papers came out, forgive me if this would have been unusual at the time, but wouldn't a 13C NMR have sorted out everything in about 5 minutes? That carbamate carbon would be both 10 ppm removed from the rest of the carbons, and would throw off the carbon count...

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2. Anon on August 15, 2012 4:11 PM writes...

I'm a Corey guy, reputation of this from the lab. What I can add is that the chem was ridiculously difficult, but we got it to work. Sometimes irreproducibility is due to technical difficulty, not that it doesn't work...

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3. Chemist of sorts on August 15, 2012 8:32 PM writes...

Isn't this essentially what Org. Syn. is? Hexacyclinol should have been caught by the refs. Sadly, experience teaches to take much of the literature with a grain of salt. Profound discovereries should be carefully checked anyway... I really don't want to see any more Pd "free" couplings reported until its established beyond any doubt.

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4. Chrispy on August 16, 2012 12:07 AM writes...

@2Anon -- Corey was the first lab I thought of when I
saw this. Maybe no one matches your talent but certainly no one matches your claimed yields. There was a joke about the "Corey 1:2 inversion" which made a 29% yield into a 92% one...

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5. Samaj-Dewar on August 16, 2012 12:32 AM writes...

The reproducibility may well work product wise but yield claimed by many groups will be very hard to reproduce. This also is a kind of reproducibility issue.

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6. Al-chemist on August 16, 2012 2:42 AM writes...

When I was post-doc'ing, I was doing organocatalysis during the years when you could just buy proline, stick it in with a couple of chemicals from Aldrich and stir at rt, then publish in JACS a week later with >90% yield + ee....good times! Owing to the overwhelming speed and simplicity of the procedures, the boss would only believe your results if you gave them to another post-doc who could successfully repeat it. We did the same thing with every paper referee'd from other groups. The result was that most of that work was pretty solid, even when reproducing stuff by the guys with poor reputations ....but then again, some of the Lewis Acid guys were pretty open about limited reproducibility of their results: in their mind, an asymmetric Lewis-acid catalysed reaction was good if it produced the claimed results 1 in every 2 times. But really, by that point it is already becoming quite a headache to attempt reproducing those results. And modern organocatalysis is the same: everybody has diverged into their own little niche area now, and it would be much harder to aufit now.

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7. Morten G on August 16, 2012 4:26 AM writes...

Well chemistry does have Org. Syn. ...

If the lab publishing the original article supplied the starting materials and intermediates it wouldn't be too much work?

And to be honest I think it should be up to the journals to check the technical data, e.g. NMRs, mass specs, xrays, and not the referees.

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8. newnickname on August 16, 2012 6:12 AM writes...

@2 Anon: I'm a bit confused by your brief post. Are you saying that you DID successfully reproduce Njar's results and obtained N-alkyl imidazoles (from heating the carbamates)?

Hmmm ... Vennerstrom reports (Synthesis, 2006, 2540) some examples that contradict Njar's claims (stable carbamates, not N-alkyls and, @1 CanChem, C13 DOES show the carbonyl carbon) but some that do rearrange to alkyl imidazoles after heating at 170 C.

As an aside, I think Njar is the guy made abiraterone, a recently approved drug for prostate cancer that got some play in Pipeline not too long ago. (September 15, 2011
Terra Slightly Less Incognita)

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9. John Li on August 16, 2012 6:44 AM writes...

@1 CanChem

I am not surprise if the C=O signal is too weak to observe. Even the 13C NMR spectrum for CDI shown on the sigma aldrich website, the C=O is just abnormally weak.

However that didn't explain the HRMS and elemental analysis

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10. Grignard on August 16, 2012 7:54 AM writes...

Great series of thoughts, Derek! Besides the more obvious traps of non-reproducibility, too many synthetic data are irritating because they are far from being reproducible even in the low gram range. These data are supposed to be "hard", well-defined number, but turn out to be quite "soft": yields, purity, ee, etc. Still, the 99% ee numbers are taken as benchmark by competing groups in the field and by referees. Some groups are aware of the limits of small scale reactions and openly point this out (Hudlicky, Synlett 2012).
My advise for everybody looking for reproducible results is to have a look at Org. Process Res. Dev., the ACS journal reporting kg- and ton-scale recipes. There is no doubt that it works.

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11. Anonymous on August 16, 2012 9:13 AM writes...

Grignard/OPR+D: there has been the occasional blemish....!
But it was tremendous comic relief.

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12. simpl on August 16, 2012 9:28 AM writes...

On the subject of reproducibility, almost every CAS number I check for existence on the internet brings up sites offering the material for sale. I feel like ordering on occasions, just for fun.

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13. Jordan on August 16, 2012 2:05 PM writes...

Reproducibility is the main reason why I (and a few other commenters, it seems) trust Org Syn and Org Proc Res Dev more than the rest of the organic chemistry literature. The chemistry isn't as novel, but it's a lot more reliable.

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14. cynical1 on August 16, 2012 2:36 PM writes...

I remember that Njar paper. I remember asking myself, 'How the hell does that work?' But I knew that a colleague of mine was trying to make analogs in that ilk so I pointed out the paper to him. He tried to reproduce the reaction, determined that he had the carbamate and not the aryl imidazole and even contacted the author. Njar replied back the first time and of course refused to admit his failure. Well my friend reproduced one of the examples in the paper and sent him the C13 NMR and LC/MS which showed that he had published crap. The guy never wrote back. I felt really bad for pointing it out to my friend because it wasted his time. If it looks too good to be true, it probably is.

Then I saw the Fisher paper when it came out and pointed it out to my friend. I laughed and told him that Fisher got a paper and a line on his resume out of it and all he got was the wrong product and had to figure out another way to make them. You don't get time in Pharma to publish why other people's published crap is just that. You just ignore it and move on, that is, until someone buys that piece of crap for 700 million dollars and you lose your job to finance it.....but I digress.

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15. Anonymous on August 16, 2012 3:47 PM writes...

so say a guy like buchwald publishes yet another 15-substrate-cat-screening with a limited functional group spectrum using a fancy phosphate, one of his mates checks it and both get a paper and a citation?

the thing with org. syn. is it just gives you the odd lucky shot of a working procedure when your substrate is reasonably close to the published example. they often use more text for conditions and remarks than for the procedure itself. such degree of optimisation and reproducibility is next to impossible for most routine organic chemistry papers.
let alone having reproduce a 1 L distillation or a 1 kg scale recrystallisation from Org. Syn. reports from >2 decades ago with the 100 mg you might have in a late stage of your synthesis...

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16. Design Monkey on August 22, 2012 1:30 PM writes...

Vincent C. O. Njar Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland,


Single author, pharmacology department. Seems to be case of pharmacologist dabbling in chemistry, which he did not understand very well.

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