A key piece of information was absent from the article concerning students who manipulated their nuclear magnetic resonance spectra (C&EN, April 21, page 32). It has been policy for many years at all American Chemical Society organic chemistry journals that evidence of the purity of characterized compounds must be provided.
The means suggested for meeting this policy are either a “clean” NMR spectrum or a high-performance liquid chromatography trace. This is necessary following the demise of elemental analysis to establish both elemental composition and purity. The article implies that the transgressions were fairly minor, but in fact, without manipulation of their data, these authors would have been unable to meet an editorial requirement for publication.
These are serious breaches of integrity, and publishing corrections is a mild punishment.
Michael PirrungApart from the lack of integrity on the part of those who manipulate spectra, it seems to me that the 'root cause' of this mess was the editorial decision that NMR spectra could be used to determine purity sufficient for publication.
Riverside, Calif.
(I wonder what Professor Pirrung thinks that the appropriate punishment should be?)
I feel old and out of touch: what brought about "the demise of elemental analysis"? I had to get EA for all my thesis compounds.
ReplyDeleteI think EA was never really all that favored relative to effort involved verses data obtained but was the best available and accepted tool to verify compounds that had legacy for application. A major drawback was most departments did (do?) not have capabilities therefore have the ship out to select labs to get done, not necessary that expensive individually yet could add noticeable costs for multiple samples per paper plus time waiting and frequent slightly off results lead to cumulative "resentment". The advent and acceptance of Hi-Res NMR and MS, which could be done in house routinely, became common place for publications. That said the customary believe is that most FDA reviewers still what EA so most people do obtain at some point to support Filing.
DeleteI got EA for my published thesis compounds as well (except the known ones). That was only two years ago! People who have never had to do this don't know what clean really means. The problem with the clean NMR standard is that there is no standard! Saying that these students would have been unable to meet a requirement for publication is ridiculous because no one rejects papers for solvent peaks. I've seen an SI in Org. Lett. where the authors didn't even remove a substantial amount of Ph3PO from their greaseball products. As for HRMS, unless you have a really clear molecular ion there is a risk of reporting a minor component or a fragment. I have run a literature procedure where the authors gave NMR and HRMS but it turned out that they misinterpreted the NMR and missed two borons in the MS!
DeleteAnd here in Castle Anthrax, we have but one punishment ...
ReplyDeleteEAs can be obtained cheaply nowadays, even for air-sensitive compounds, and I think they should still be the proper method for showing bulk purity.
ReplyDeleteOnly in cases where EAs cannot be obtained for some reason or bulk purity is not an issue should other methods be used. In my opinion, bottom line is that NMR and MS will never substitute for EA. Will either of those tell you if you have 10% NaCl or silica gel impurity in your compound? You won't see it in NMR, and you usually don't look in those regions in MS, you just look for the ions you want in MS. Solvents/chemicals are added to both techniques (NMR solvent, or solvents/ionization additives to MS).
If someone can explain exactly how NMR and MS substitute for EA in terms of bulk purity (not just "hey, my compound is the only thing we can see with this technique"), I would love to hear it.
Best way to tell bulk purity is NMR and EA together. MS is useful diagnostic tool, but useless for purity. Actually one of the best ways to assess purity is still melting point (if the material is a solid at a convenient temperature). DSC is cheap and easy to run, and if the melting transition is sharp and symmetric, that's a tell tale sign of purity. Actually we won't send a compound for EA until we are comfortable with the DSC even after NMR comes back clean. I can understand why people have soured on EA though. It actually requires patience and skill to properly purify an unknown compound so it will pass within acceptable limits.
ReplyDeleteI really never did understand the whole idea of putting NMRs in the ESI. First, I want to see the baseline. That's where the impurities are going to be anyway. The NMRs people put in the ESI are barely visible.
"Apart from the lack of integrity on the part of those who manipulate spectra, it seems to me that the 'root cause' of this mess was the editorial decision that NMR spectra could be used to determine purity sufficient for publication."
ReplyDeleteIf EA was still required by journals, then wouldn't this just push people to (quoting a famous recent example) 'just make up an elemental analysis'? It's significantly less work to submit fake EA; no Photoshop required. (I will concede that there may be a higher moral barrier to faking an EA vs manipulating and NMR – i.e., outright fabrication vs what people might see as 'cleaning up'.)
No argument that EA is a far better demonstration of purity than NMR, but I'm not convinced about the connection to data manipulation.