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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: derekb.lowe@gmail.com Twitter: Dereklowe

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March 19, 2014

More Things Synthetic Chemists Hate

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Posted by Derek

I enjoyed this post over at Synthetic Remarks on "Five things synthetic chemists hate". And I agree; I hate all of 'em, too. Allow me to add a few to the list:

1. The Mysterious Starting Material. How many times have you looked through an experimental section only to see a synthesis start cold, from a non-commercial compound whose preparation isn't given, or even referenced? One that doesn't seem to have any foundation anywhere else in the literature, either? I think that this is a bit more common in the older literature, but it shouldn't be happening anywhere.

2. It Works on Benzaldehyde; What More Do You Want? What about those new method papers that include a wide, diverse array of examples showing how versatile the new reaction is - but when you look at the list, you realize that it's full of things like cyclohexanone, benzaldehyde. . .and then 4-methylcyclohexanone, p-fluorobenzaldehyde, and so on? Turns out that the reaction lands flat on its nose, stretched out on the sand if there's a basic amine within five hundred yards. But you have to find that out for yourself. It ain't in the text.

3. The Paper Chase. In these days of humungous supplementary info files, what excuse is there to write a paper where all the reactions use one particular reagent - and then send people back to your previous paper to learn how to make it? Sure, reference yourself. But don't march everyone back to a whole other experimental. Are authors getting some sort of nickel-a-page-view deal from the publishers now that I haven't heard about?

4. If I Don't See It, It Isn't There. When I review papers, one of the things I end up dinging people about, more than anything else, is the reluctance to cite relevant literature. In some cases, it's carelessness, but in others, well. . .everyone's seen papers that basically rework someone else's reaction without ever citing the original. And in these days of modern times, as the Firesign Theatre guys used to say, what excuse is there?

5. Subtle Is the Lord. Once in a while, you find an experimental writeup that makes you wrinkle your brow and wonder if someone's pulling your leg. The reaction gets run at -29 degrees C, for 10.46 hours, whereupon it's brought up to -9 and quenched with pH 7.94 buffer solution. That kind of thing. If you're going to put that Proustian level of detail in there, you'd better have a reason (Proust did). No one just stumbles into conditions like that - what happened when you ran your reaction like a normal human, instead of like Vladimir Nabokov on Adderall?

Comments (38) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. Lyle Langley on March 19, 2014 7:29 AM writes...

Much like your #2 (sorry, really didn't mean it to sound like it reads...), back in the day when everyone and their brother were testing out catalysts using diethyl zinc additions to benzaldehyde. Boy could people get the additions to go in high yield and ee; but they wouldn't work on anything else. There for a while in the late '90s it seemed to be the rage (even in my group for a short time).

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2. Curt F. on March 19, 2014 7:43 AM writes...

I have quite a mixed mind on #4. Yes, science works better when authors are widely read and cite all appropriate literature. But if they don't? In that case are citations supposed to the reflect what actually influenced the authors (which would improve citations as a metric of researcher performance) or should the citations reflect all relevant literature the authors can find at the time of writing or review (which would improve things for readers)?

I've definitely been a reviewer who struggled to understand why paper wasn't citing an obvious reference ( and no not be one of my own) but I've also been an author confused by reviewer demands to cite papers that weren't high profile, were only tangentially related to my topic, and which I had never read before.

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3. dearieme on March 19, 2014 8:57 AM writes...

@Curt F: when a reviewer asks you to cite a paper by Roger F Pipeclencher et al, it's pretty tempting to reply "Certainly, Roger".

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4. Erebus on March 19, 2014 9:18 AM writes...

#1 is a commonplace annoyance in steroid synthesis. A lot of work on the steroid scaffold was done in the 'old days', and it's not uncommon to see a paper's 'synthesis' start from a very obscure compound, sometimes even secosteroids & similar open-ring compounds, without any information on how to get there in the first place.

There are many other compound classes, as far as I am aware, that don't have it as bad. Fortunately!

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5. Henry's cat on March 19, 2014 9:21 AM writes...

Sometimes a starting material will have an abysmal yield, and if you are working on a number of steps, if you have a 20%er in your first step, then your overall yield for the route is well and truly tooled from the start.

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6. A Nonny Mouse on March 19, 2014 9:25 AM writes...

...and don't forget the reagents that the group in question has access to, but no one else. I had this twice following a Japanese paper- the amine in that solvent at that very high concentration was not available in Europe and the low temp radical initiator was only available in 25kg sacks shipped in dry ice.

Work your way around this and find that the yield is only 30% (of nice white crystals) rather than 85% of an oil (which, on viewing the supplementary data, was mainly tributyl tin residues).

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7. mass_speccer on March 19, 2014 9:36 AM writes...

Similar to 6. A Nonny Mouse....

Catalysts that the group has made that no one else has. e.g.

"A was converted to B in 99% yield and 99% ee using Pd[L]x as catalyst"

Where [L] is a ligand "readily available" in about 17 steps...

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8. Anonymous on March 19, 2014 9:56 AM writes...

I hate seeing representative procedures in methodology papers, especially when the other entries have completely different times, temps, solvents, etc.

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9. CMCguy on March 19, 2014 9:56 AM writes...

I somewhat disagree with stance #5 regarding level of detail reporting as although it appears extreme precision relative to typical lab records if you saw experimental write up that simply said "chilled in IPA/CO2 bath overnight then quenched into ice bath with neutralization buffer" would you know more or less what your best conditions should be. It is atypical when the actual important parameters are determined and described except in a thorough reaction development paper. If a reaction didn't work out well I would rather have TMI where I can apply more common sense judgement verses having a set of over generalized conditions that will likely require greater amount of work to figure how to make successful.

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10. Yossarian on March 19, 2014 10:27 AM writes...

Experimental: ... The yield was 7.12 g (98%). Analytical sample was purified by preparative HPLC followed by crystallization. 1H NMR: ...

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11. The Iron Chemist on March 19, 2014 10:45 AM writes...

When I was a postdoc, I was working on some TACN syntheses. I found an interesting derivative that had a synthesis that was claimed to be in one paper, which directed the reader to another paper, which directed the reader to another paper, which directed the reader to yet another paper, which didn't actually contain the synthesis at all.

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12. anon the II on March 19, 2014 10:45 AM writes...

I've been trying to make some Near IR dyes lately. From the experimental write-ups, it looks like you could whip out a gram or two in a week. If you try to buy the same products, they go for something like 5 mg/$2000 or more, at 80% purity from some odd source. There's an obvious disconnect here. After a week of trying to follow literature procedures and not getting very far, I'm beginning to suspect that these write-ups are leaving out a few details. I guess the question is if and when I write these things up, will I just cite the literature or will I try to provide some insight into how to actually make them.

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13. fluorogrol on March 19, 2014 10:51 AM writes...

@dearieme: Having worked 'behind the curtain' of peer review, I can tell you that it's infuriatingly common for reviewers to write some brief (sometimes brief to the point of uselessness) comments and then demand that three of their papers are cited before acceptance.

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14. Jacob on March 19, 2014 11:00 AM writes...

Oh, those generalized procedure papers! 40 different compounds sharing some structural feature and they give one diagram of a carbon atom with R, R', R'', and H attached to it followed by a table of Roman numeral and letter designated variants that cross reference each other.
Compound XIII(c): same as (XIII(b)) exept R'' = COO- K+
Compound XIII(b): same as XIII(a) except R'=R''=CH3
Compound XIII(a): see compound VII(f) with R=X (where X is either a halogen or a nitrile)
And so on.
And then, of course, the starting material is prepared according to a method in Justus Liebig Annalen Der Chemie from 1863.

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15. Anonymous on March 19, 2014 11:13 AM writes...

I hate the terminology in synthetic papers that is used to transition from 'hypothesis to initial result' and 'from bad result to better result', such as:

"Pleasingly..."
"Gratifingly..."
and especially,"To our delight..." or "Delightfully"

Used far, far too much, and I don't like the way it reads or sounds at all.


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16. Academic Malpractice on March 19, 2014 11:22 AM writes...

I can think of a certain big wheel at Princeton who is the personification of #4...

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17. Cato the Elder on March 19, 2014 12:23 PM writes...

More along the vein of Derek's step-count post the other day, I always feel a bit cheated when I read "10 step synthesis" and then find out the starting material is not something commercially available but also takes another 10 steps and it just so happens that someone already made it before... as if anyone really falls for that little trick

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18. Cato the Elder on March 19, 2014 12:28 PM writes...

Also, @15, I agree those have been a bit overused. How about throwing in some new ones in your next publication? I'm thinking: "Gleefully, we threw all of material into the next reaction"

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19. DCRogers on March 19, 2014 1:24 PM writes...

Forward references to a "forthcoming paper", which never seem to forthcome.

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20. Anonymous on March 19, 2014 1:39 PM writes...

18: Yes, thank you. I'm glad I'm not the only one who noticed this. Gleefully is a good one.

Or some weird, extreme one would be funny: "To our mania..."

It should work both ways, so I'd also like to see some negative ones for bad results, such as "Sickeningly..." or "To our disgust...", "To our shame...", "Repulsively...", "Grievingly...".

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21. mamid on March 19, 2014 2:41 PM writes...

@20: You just made my day, I can go home with a smile on my face. "To our disgust...", indeed!

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22. TexChem on March 19, 2014 2:56 PM writes...

@Jacob

Chances are the Liebig chemistry would work exactly as described though.

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23. Jacob on March 19, 2014 3:41 PM writes...

@TexChem,
You have a very valid point, as I have had good experiences with Annalen aside from the occasionally Byzantine Hochdeutsch.
So, I will retract the reference to J. Liebig and substitute "some obscure Soviet central Asian chemistry journal".

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24. Anon on March 19, 2014 4:15 PM writes...

I used the word bittersweet in a recent paper :o

http://www.ncbi.nlm.nih.gov/pubmed/23574014

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25. Nick K on March 19, 2014 11:28 PM writes...

#14 Jacob: This is one of my pet hates too. Particularly bad are J Chem Soc papers from the 50's and 60's. Quite often, there would be a benzene ring with six R groups and a huge table of Roman numerals as a key.

Another gripe with these old journals: the complete lack of a synthetic scheme with structures and arrows.

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26. Lloyd T J Evans on March 20, 2014 2:10 AM writes...

Something I find absolutely infuriating in journal articles is references which go absolutely nowhere. Let me be clear: I don't mean references to papers in ancient or obscure journals. Those are irritating to be sure, but are still possible to find with a bit of laborious digging.

No, what I mean is when you find something intriguing in an article, with a reference number attached. So you flip to the references section to find it. But then you find stuff like:

"Doe, J. et al. Work in progress."

"Doe, J. et al. Unpublished work."

"Doe, J. et al. Publication pending."

Or any other similar variation on this theme. Now perhaps I'm missing something here, but surely the primary purpose of a reference is to enable any reader to look up further papers to confirm or expand upon the information in the original article.

However, it seems to me that "references" of the type I described above are completely worthless. In fact (to shamelessly paraphrase Derek), whenever I see such a pointless reference used in any paper, I always want to punch whoever thought it might be even remotely useful.

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27. Wim Libaers on March 20, 2014 7:20 AM writes...

The best I've ever had the "pleasure" of reproducing was one where the authors hadn't even quite figured out where one of the starting materials, gallium chloride, was GaCl3 or GaCl4 (one of those seems unlikely to exist as stable molecule, and doesn't occur elsewhere in the chemical literature, so that was a useful hint). Both names were used as if they were the same in the article.

But hey, at least it was an excuse to play with sodium, napthalene, GaCl3 and phosphorus in a solution in boiling glyme (the reported temperature for the experimental conditions was absurdly high, I think they confused degrees Celcius and Kelvin, but it was a few years ago, I don't recall the exact details).

It didn't really work, and I don't think we ever got the black/reddish residue out of the flask either.

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28. TexChem on March 20, 2014 8:52 AM writes...

@Nick

While I totally agree with you that interpreting these tables is a challenge, bear in mind that chemical drawing programs were not used routinely until the late 80's and so authors had to draw these by hand using templates (in 50's and 60's). Later transfers made this a little easier, but take it from someone who did it using templates and ink pens to get "quality figures" was a pain and hence the sparsity of schemes and the liberal use of R.

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29. anonymous coward on March 20, 2014 9:29 AM writes...

Russian journals still love the "Markush with a metric %$^&ton of variable groups" method of structure representation. It goes really well with the (Roman numeral)(lower-case Roman letter) method of denoting compounds, which gets really annoying when IIa and IIIa do not correlate to one another (whereas in most other journals the small letter implies common structural origins) - IIa goes to IIIc-e, while IIIa and b come from somewhere else. Deconvoluting it is like untangling spaghetti.

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30. GladToMoveToProcess on March 20, 2014 10:00 AM writes...

Sort of like Derek's #5: there was a paper in JOC, I think, within the last year or so, where the last step of the synthesis had an experimental to this effect: "Reagent X (7 microliters) was added dropwise over 1.5 hours...." It may have been 9 uL, but whatever, it was remarkable.

And re comment #20: a referee got upset when I wrote "To our horror, the stereoisomers could not be separated;" had to clean that up.

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31. Hano3s on March 20, 2014 11:20 AM writes...

Looking for this one specific conversion in Scifinder-or-the-like, with tolerance for this and that functional group. Then getting five results of in two of which the desired product is an undesired impurity formed in 0.9 %, the third is an untranslated Russian patent, the fourth is in a journal you can't access and the fifth is in a journal without experimental details. Grrrrrrr.

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32. ajsp on March 20, 2014 12:39 PM writes...

Here's a JACS paper with NO apparent details of the synthesis (or reference to another paper giving them):
http://pubs.acs.org/doi/full/10.1021/ja105921g
(DOI: 10.1021/ja105921g)

They don't even bother to make something up, or reference something fictional...

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33. Anon on March 20, 2014 8:55 PM writes...

@26 For some reason I've been coming across a lot of 'internal communication' references lately. For the next paper I write I'm tempted to cite a 'hallway conversation' and see if that gets by review...

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34. Nick K on March 21, 2014 4:27 AM writes...

#28 TexChem: Laziness is no excuse: there are papers from that era with plenty of structures and clear synthetic schemes.

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35. Anonymous on March 21, 2014 5:34 AM writes...

1: Found that one out the hard way: 2 weeks, glove box, 2 rounds of expensive stoichiometric reagents.....

2: What about revolutionary catalysts for 'asymmetric Diels Alder' reactions, which only work with cyclopentadiene

3: tied to 1 - the original synthesis was 3 or 4 refs back.

4: A certain person once rejected one of my papers based on the fact that I referenced only 8 of his 9 publications in the area. I've also had flat rejections with no reason given from (presumably) the same Princeton academic mentioned by #16. Who also seems to forget that we published similar reactions when he publishes.

5: i'm often more concerned about the lack of detail in papers. I had one once where a reagent was added 'slowly'. Rate of addition actually turned out to be really important in terms of product distribution (mono- vs. bis-) surely the guys that inventerd the reaction would have thought of that?!!??

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36. Secondaire on March 23, 2014 11:01 PM writes...

The one that really gets me (and I suppose is more of an unfortunate coincidence than anything) is when the only other reference in the literature to the starting material you need is a) something that's in a language that neither you nor any of your colleagues can translate, or b) is a vague experimental detail in a "characterize every derivative of quinoline-2-carboxylate known" paper from 1938.

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37. NitricAcid on March 26, 2014 6:45 PM writes...

When I was a grad student, a fellow named Eisenberg had a reputation for giving very little detail in his experimental section (this was referred to as the Eisenberg uncertainty principle). He'd have a communication announcing the synthesis of an interesting organometallic compound (experimental details will be available in the forthcoming paper). Then he'd publish the paper- "Compound 1 was synthesized as detailed in the communication."

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38. Anon on April 14, 2014 9:41 PM writes...

I once followed a lit procedure that specified that the reaction could only proceed for EXACTLY 8 minutes. Turns out to be true, didn't work with 7, didn't work with 10.

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