Friday, 18 March 2011

Hexacyclinol - NMR spectra vs plain images

I’m sure that many of you are aware of the infamous controversy over the total synthesis of Hexacyclinol . There are a plethora of arguments, from the purely synthetic chemical point of view to the spectroscopist perspective, which both put in doubt the veracity of aforementioned total synthesis. You can find, at the end of this post, a list of references that may be of interest on this subject. In this particular post, I would like to comment on several interesting aspects from an NMR standpoint.

In the original article’s “supporting information”, one can find the spectra of Hexacyclinol and derived compounds. I believe that the key to the controversy here lies in the fact that these spectra are found solely as plain images, that is, all the relevant spectral information that could have provided more conclusive proof over the authenticity or not of the total synthesis of this compound is lost.
Let’s consider for example, the image of the Hexacyclinol spectrum:

I have cut the central vertical area of the image in order to visualize the highest intensities as well as the smallest ones together. The objective is to simply appreciate with clarity the level of 13C satellites intensities in the case of the CHCI3 signal. The level is indicated by the red horizontal line which would correspond, approximately to an intensity of 32, that is, a ~0.55% of the intensity of the CHCI3 signal.

At first glance, one cannot observe such signals from the 13C satellite. Is this a conclusive reason to assume that this spectrum is really a fake, that is, a spectrum that was created synthetically? Of course, I’d say it is not conclusive but it could be an indication.

In principal, I would say that the SNR of this spectrum seems good enough for the 13C signals to be observed; not only in the CHCI3 area but rather that they cannot be observed in any part of the spectrum. I can only come up with two reasons that justify the absence of those signals:
  1. On the one hand, the author could have acquired the spectrum using a pulse sequence that removes the 13C signals (e.g. 13C GARP broadband decoupling). I’d say this is highly improbable given that, if this was so, it would seem reasonable that the author would have specified in the article the use of such decoupling technique. In any case, if the complete “raw data” acquired were available, then the pulse sequence could be analyzed. Of course, this would not be a conclusive proof either since the pulse sequence is generally found in a text file which could be manipulated easily by any editor (unless it is digitally signed).
  2. On the other hand, the fact that the 13C signals are not observable may be due to the acquisition settings, more specifically gain settings in the case of very strong spectra. The problem lies in when there is not enough noise to fill at least ~6 ADC steps, you start rapidly losing small peaks and, of course, the noise starts looking weird, kind of binary, which can be actually perceived in this case. In any case, I don’t think this would really justify the absence of the 13C signals. If this is what happened during the acquisition, it would never be so perfectly void of satellites or have a perfect baseline and phase, according to my opinion.
Therefore I insist, if the raw data were available, more effective analysis could be carried out. For example, one could analyze the line widths of isolated signals. If all of them were the same, this would put us on that track that the spectrum was synthesized given that in real life, this is something very difficult to occur.

In summary, it is very difficult to reach conclusive results working with plain images. Once the spectra have been acquired, transforming them into images only result in an irreversible loss of important information. I believe that publishers should oblige authors to submit spectra/original FID’s (including all the files with additional metadata) to avoid any type of loss of relevant information.

  1. Total Syntheses of Hexacyclinol, 5-epi-Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif
  2. Total Synthesis and Structure Assignment of (+)-Hexacyclinol
  3. Predicting NMR Spectra by Computational Methods: Structure Revision of Hexacyclinol
  4. Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited
  5. Hexacyclinol? Or Not?
  6. Hexacyclinol: A Forensic Case
  7. The Hexacyclinol incident
  8. Hexacyclinol: Case Closed

1 comment:

stan said...

Hi Carlos. Just a fast one in support of your call for raw data.
Some time ago an Editor of Angewandte Chemie send me an e-mail asking whether cheating on spectra was a frequent problem in NMR community. I told him that I did not think so and that it was extremely difficult to fake a spectrum in a way an expert would not notice.
I also asked why he was asking and the following picture unfolded:
Apparently there was a paper which got through the referees and was accepted and ready for printing. Which is when somebody with access to a preprint noticed that one or more spectra were faked and warned the principal author, who withdraw the whole thing. Apparently, one of the authors, perhaps a student, faked the spectra and did not tell the others.
I thought that your readers might like the story since it shows a somewhat unusual "twist" to data faking.
Ciao, Stan