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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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November 29, 2007

Neat! Wish It Were True!

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Posted by Derek

annulene.gifThere’s a rather embarrassing note leading off the latest issue of Angewandte Chemie. Two recent papers (2007, 2006) had reported the synthesis of some rather weird 12—membered rings, the diazaannulenes shown here. They made them from dinitrophenyl pyridium salts and primary amines, with the pyridine ring unraveling oddly along the way. Too oddly.

Professor Manfred Cristl of Wurzburg, who apparently knows his pyridinium chemistry pretty well, recognized this as an old way to make further pyridinium salts, not funky twelve-membered rings. He recounts how over the last couple of months he exchanged awkward e-mails with the two sets of authors, pointing out that they seem to have rediscovered a 100-year-old reaction, and have they really looked at their spectral data closely, eh? Both groups have admitted their mistake – the data match up wonderfully with the known pyridinium compounds, unfortunately, so there’s really no other way out – and retractions are appearing.

He raises some broader points, though: first, there’s the obvious problem that this whole thing should have been caught by better literature searching and analytical chemistry. These arresting structures deserved more than a quick NMR and LC/MS, and they deserved more than what appears to have been a not-very-thorough look through the prior art. There’s a bigger problem, though, which fans of the LaClair imbroglio will enjoy. Note the exasperated tone of the following, which comes across in a very German fashion:

”A further question refers to the reviewing of the above papers. Presumably, at least four referees were entrusted with this duty, two of Angewandte Chemie and two of Organic Letters. They have provided conclusive evidence for their lack of knowledge of heterocyclic chemistry. However, the referees are probably chosen by the editorial offices according to the specialization of the corresponding authors and, thus, have the same gaps in the knowledge as the authors. In consequence, if the authors present results remote of their main projects, extreme misjudgments are inevitable. . .”

So, once again, Angewandte Chemie's reputation is upended by sloppy refereeing and editing. This time, though, they run an article berating themselves. Progress, I'd say. . .

(Note: update on this story here, and why it might have happened, here).

Comments (29) + TrackBacks (1) | Category: The Scientific Literature


1. dtb on November 30, 2007 4:16 AM writes...

It's every bit as entertaining as Phil Baran's current Angewandte ASAP (DOI: 10.1002/anie.200704576 ), in which he notes that several authors misinterpreted the spectral data for a series of pyridinium salts formed via the Chichibabin pyridine synthesis. He 'helpfully' includes their NMR spectra in his supporting information alongside his own spectra of the same compounds, pointing out the other guys' misassigned peaks...

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2. Egon Willighagen on November 30, 2007 5:27 AM writes...

This is a brilliant example why Open Data matters! And that keeping those properties tied up in articles only is really bad for science. Were all those properties freely available, these two author sets would have likely discovered their misinterpretation themselves.

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3. Hap on November 30, 2007 11:06 AM writes...

The problem wasn't that the data were unaffordable or unavailable - if that were the case, then freely available data would have helped correct the error more rapidly. The problem was that the reviewers and the people doing the chemistry (and most of the people reading the article, likely including the set of people who would have had access to the article were it less expensive) weren't able to correctly interpret the data. Only a few people know enough pyridine chemistry to figure out what was wrong, and they were already likely to have had access, so improving availability of the data would not have helped. This mistake argues more for requiring stronger data to support the hypotheses of papers and for more critical reviewing to assure that the data and the hypothesis conform to one another (or for more appropriate reviewers) than for improved availability of the data.

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4. eugene on November 30, 2007 11:13 AM writes...

I was looking at that structure for a really long time, thinking of how you can get a 12 membered anti-aromatic system out of two 6 membered aromatic rings... But I guess it's not that simple. Despite the fact that you can break pyridine's aromaticity under certain conditions. I'll have to read the original now for the justification.

This sucks because if I were to have a paper in that journal that I worked very hard on getting crystal structures, etc... it would cheapen it now. Although I guess JACS and Science have their own share of scandals, some Chinese group retracted from JACS a la Sames half a year ago, but it doesn't damage those journals' credibility as much.

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5. Jose on November 30, 2007 11:35 AM writes...

From the OrgLett paper, "Scheme 2 shows a plausible preparation mechanism for the diaza[12]annulene dichloride..."
Ughhh. I suspect postulating that mech on a Cume exam would lead to some rather caustic responses....

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6. Karl Hungus on November 30, 2007 1:30 PM writes...

It's cases like this where I say "There, but for the grace of God go I". I think the guy delivering the smack-down was too harsh. I mean, they were wrong; they screwed up. You have every right to correct it. Fine, you get to crow a bit since you caught it, but to partial out blame to everyone, to state that everyone who reviewed the paper is an ignoramus because they aren't familiar with pyridine chemistry 104 years old--come one, dude, loosen up. They fucked up. They were expecting a result, got spectra consistent with that result, and published. What a tough coincidence that they had aggregates in the high-res EIMS and had an NMR spectrum consistent with the product they proposed. Full moon I guess.

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7. Karl Hungus on November 30, 2007 1:31 PM writes...

It's cases like this where I say "There, but for the grace of God go I". I think the guy delivering the smack-down was too harsh. I mean, they were wrong; they screwed up. You have every right to correct it. Fine, you get to crow a bit since you caught it, but to partial out blame to everyone, to state that everyone who reviewed the paper is an ignoramus because they aren't familiar with pyridine chemistry 104 years old--come one, dude, loosen up. They fucked up. They were expecting a result, got spectra consistent with that result, and published. What a tough coincidence that they had aggregates in the high-res EIMS and had an NMR spectrum consistent with the product they proposed. Full moon I guess. Let's chalk it up to that.

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8. Great Molecular Crapshoot on November 30, 2007 2:12 PM writes...

I've not looked at the articles so my question may have been answered already. Wouldn't a 12-membered ring have some protons 'inside' the ring and wouldn't NMR show these to be very different?

I don't agree with Egon's point that this is a brilliant example of why open data matters. However, this is only because there are much better examples. I am referring specifically to analyses of in house data sets by pharma company researchers using in house software and undefined descriptors.

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9. Hap on November 30, 2007 2:17 PM writes...

There's no reason to be rude about it, but the formation of those compounds is unusual enough that one ought to ask for more than NMR and MS data - a crystal structure would be nice (though there's no guarantee that you can get one), or ring current data (how do you tell?), for example. If you make an extraordinary claim, you ought to have pretty substantial evidence, and there doesn't seem to have been enough to do so. Another hope would be that the authors had more thoroughly checked other possible structures for their products before publishing (asking themselves what have other people seen in related chemistry) - so that they wouldn't be embarrassed like this.

Considering that the LaClair affair revolved around the lack of sufficient (or any) data to support the claims of the paper, AC might have done better to be more careful as well - more data wouldn't protect against fraud, but against incorrect chemistry it would be a more effective barrier to embarrassment. I don't know if journals have fine enough knowledghe of research interests to find someone to review the paper without conflict, but that would have helped as well.

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10. Karl Hungus on November 30, 2007 2:58 PM writes...


I agree, more evidence may have been warranted. But Christl's claim that the referees "have provided conclusive evidence for their lack of knowledge of heterocyclic chemistry" is hypocritical, not to mention contemptible. That, I think, is an extraordinary claim requiring extraordinary evidence. Christ, Christl! They retracted their results; they didn't commit scientific fraud. Just because you catch someone who has made a mistake doesn't give you a soapbox to pontificate with an air of authority about all things related to scientific inquiry and reporting. He's the guy who kicks a man when he's down just to elevate himself.

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11. Hap on November 30, 2007 4:03 PM writes...

If I had seen the mistake and knew enough to correct it, I would hope that I would have chosen a nicer way to do it. I don't think I would have gone out of my way to be mean, and that is what Christl is probably doing here (and perhaps taking advantage of his position for self-aggrandizement - there seem to be an awful lot of professors who don't play well with others). I didn't think that the mistake was unavoidable, though, and that the authors and Angewandte and OL) should have done more to avoid it.

I don't think Christl will be getting any papers in ACIEE anytime soon (if he was going to be getting them there anyway).

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12. Jose on November 30, 2007 4:51 PM writes...

I agree; the wording of the Christl response is a little over the top. However, I try to imagine myself with the original data in hand, and the mental flow to such an unexpected, novel, and unusual structure. I would make *damn* sure I had everything right, including every 2-D experiment I could think of, and a very extensive lit. search.

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13. Jose on November 30, 2007 5:45 PM writes...

Sorry, I am going to revise my thoughts. Staggeringly sloppy research and refereeing, on all fronts. Simple SciFinder reaction search: phenyl-pyridinium salt + aniline (substruc of more complex) -----> 30 papers (minus papers in question). One *abstract* even mentions "Zincke reaction," and almost all are not obscure. eg JMedChem, 42(17), 3342-3355; 1999 has essentially the exact reaction in the 2006 OrgLett.

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14. weirdo on November 30, 2007 6:27 PM writes...

I agree with Jose here. These were terrible papers. Three minutes on SciFinder would have revealed the problem, not only for the authors but for those editors and referees unfamiliar with the field. This is NOT obscure chemistry.

Too, one of the PIs of the two papers was involved with a pretty (in)famous case in the late '80's, on the OTHER side. Somebody may have thought he had this one coming.

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15. SRC on November 30, 2007 9:50 PM writes...

The problem is with scientific training in general (in molecular biology, most notably). An extraordinary conclusion requires a commensurately extraordinary level of proof (global warming adherents please note); a hoofprint does not suffice to prove the existence of unicorns.

That level of proof was not forthcoming here, and therefore the referees did not do their jobs, their knowledge/ignorance of heterocyclic chemistry notwithstanding. The requisite level of proof here would require the authors' explanation as the only viable one, not just one of the many consistent with their results. Occam's Razor and all that.

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16. Nick K on December 1, 2007 7:59 AM writes...

This fiasco reminded me of my time at at UEA many, many moons ago. Katritzky's influence there was still strong, and so we did a lot of pyridine chemistry. One of the mechanistic problems we were set was precisely this reaction. Nucleophilic attack on pi-deficient heterocycles followed by ring closure is absolutely classical. Why didn't the referees spot this?

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17. Metalate on December 1, 2007 11:00 AM writes...

Has anyone noticed that OL has removed all but the first page of the Supporting Info from the 2006 paper? Is this policy on retracted papers? And if so, why?

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18. Wavefunction on December 1, 2007 4:57 PM writes...

While Christl's detective work is admirable, I think he is being too harsh towards the reviewers. I think this is definitely an honest mistake.

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19. milkshake on December 2, 2007 12:37 AM writes...

It was a piece of wishful thinking and poor lit search on the authors side - so it qualifies in the category of crackpot articles.

I remember an entertaining crackpot article claiming a discovery of a special high-boling allotrope of water that only forms in capilaries under special circumstanes - and had high boiling point and other changed physical properties. Then it was pointed out that the special water had the same spectra as sodium lactate from human sweat...

Journals always get some strange stuff like this and the higher profile the journal has the more responsible has to be about reviewing the submissions: It is the job of revieweres to ask tough queastions

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20. Wavefunction on December 2, 2007 7:14 PM writes...

I think it is a little too much to compare this misunderstanding to the purported discovery of "polywater"

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21. Jan on December 6, 2007 2:01 PM writes...

The case is now in the German mainstream media:,1518,521646,00.html

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22. Hap on December 6, 2007 2:45 PM writes...

It's not as big as polywater, but it's probably worse - there wasn't enough data to back the current authors' conclusions, and methods were available to confirm or deny their conclusions which weren't used while in the case of polywater neither of these may have been true (I don't know if NMR or some other method would be sensitive enough to pick up the contaminants responsible for polywater, but something other than NMR and MS would have been good to check the presence of the macrocycles in this case). In addition, people hadn't seen polywater before, while the reactions invoked here (Zincke reaction) had been seen before many times and remarked in the literature.

I don't think the authors meant to deceive anyone, and the reviewers ought to take some blame for insufficient checking, but the authors were fairly sloppy not to have questioned their results more stringently. It was an honest mistake but also an insufficiently smart one.

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23. milkshake on December 6, 2007 3:19 PM writes...

They could have easily seen it from their MS: You can look and distinguish if a signal is 2M(2+)/2 or if it is M(+): by the isotope distribution. If you can't see things half unit apart because of natural D abundance, then it can't be 2M(2+)/2

The problem is they were not looking very hard.

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24. eugene on December 6, 2007 5:01 PM writes...

Like the letter says though, aggregates can form and can be detected by MS as 2M(2+)/2, and that was the main argument of one of the authors.

According to the Spiegel, there is a thing in Nature on it as well. I'll have to take a look. Still, I doubt that, according to the Spiegel and Christl, researchers have to review a paper a day and simply don't have time to check literature due to time constraints. If you're a prof, you should set apart five to ten hours a week to read literature and books. I should do that myself actually.

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25. TWYI on December 10, 2007 7:39 PM writes...

With regards to Baran's Chichibabin reassignment, the originals have now been retracted

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26. psychic readings on December 11, 2007 1:48 PM writes...

This was really interesting. Thanks

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27. Tony Landis on December 11, 2007 3:33 PM writes...

Well, nobody is perfect ;)

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28. opsomath on December 16, 2009 10:45 AM writes...

No one questions the sloppiness of the original report. However, I've worked for those professors before who seem to have made a career of surveying the literature and finding things that are wrong which other groups have reported.

I know it's part of the scientific process, and whatnot. But it is strongly correlated with being a bastard that I wouldn't want to work for again. If I find a prospective advisor has a paper like this on his CV, I'm gonna keep walking unless I'm starving in the streets.

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29. Gerry Belinsky on August 18, 2012 9:43 AM writes...

Wow that was unusual. I just wrote an really long comment but after I clicked submit my comment didn't show up. Grrrr... well I'm not writing all that over again. Anyway, just wanted to say great blog!

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Over at Corante’s In the Pipeline , organic chemist Derek Lowe has a post that vividly demonstrates one of the unfortunate realities of the research environment: researchers can spend years “discovering” what’s already been disc... [Read More]

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