Field of Science

Hexacyclinol: Case Closed

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Seems that hexacyclinol is finally dead and buried and the tomb has been sealed. If anyone had any doubt that there was something wrong with the original structure, this paper should resolve it. For those who have had the good fortune of not hearing about hexacyclinol, see the links at the end.

In any case, the present authors from Italy simply calculate H1 chemical shifts and coupling constants for the original disputed structure (1) and the newly proposed and calculated structure (2). Recall that one of the things James La Clair claimed when John Porco synthesized what Scott Rychnovsky felt (Yes, it does sound like one of those convoluted Shakespearean chains of people) was the correct structure was that the two different structures could possibly give rise to the same or extremely similar NMR spectra.

Yes, it's probably true that in the infinitely large universe of organic compounds one could possibly locate two compounds which could give the same NMR spectra. In real life, such a possibility for two complex compounds that look so different is very unlikely. However, the assertion that this could be so is a testable and falsifiable hypothesis and therefore a good one.

In the present paper, the Italian group finally tackles the problem using a set of high-level calculated NMR spectra that include H1 chemical shifts, coupling constants, and even COSY plots at the DFT level. The answers are unambiguous and clear; Porco and Rychnovsky's hexacyclinol gives much smaller errors between measured and calculated parameters compared to La Clair's "hexacyclinol". At the same time, there is some striking similarity between many of the NMR parameters. In the end though, a competent organic chemist would be able to tell that the spectra belong to different structures. As the authors put it rather clearly,
The structure of hexacyclinol is confirmed to be (2). Furthermore, if (1) had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of (2) as to guarantee their distinction.
Short of a miracle that the famed Bionic Brothers could spring now, I don't see what Dr. La Clair can do to validate his original proposal and synthesis. This should also again be a question for Angewandte Chemie who published the paper; I am sure all of us are curious to know what happened there.

I have talked on this blog several times before (see below) about computationally calculated NMR parameters coming of age, and this paper should reinforce their tremendous power in resolving confusion between organic structures. H1 chemical shifts can now be predicted to within a remarkable 0.1 ppm accuracy. Hopefully these studies should now encourage the widespread use of the relevant tools in organic chemistry.

Previous posts on hexacyclinol and computational prediction of NMR data: here, here, here, here and here

Update: Also discussed at In The Pipeline and The Chemistry Blog. As mentioned in the comments, I too find it remarkable that Angew Chem has not published some kind of explanatory note by now, after all the blog and news publicity that the issue got.

Giacomo Saielli, Alessandro Bagno (2009). Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited Organic Letters DOI: 10.1021/ol900164a


  1. Impressive ! Are the NMR calculations done using spectra from known compounds to 'tune' parameters, or are the NMR data calculated a piori?

    You mentioned in a previous answer that force fields from proteins (which were turned from actual data) weren't very good in predicting binding to RNA. For why I was interested in this in the first place see the Chemiotics post of 9 Feb "The further uses of redunancy" -- particularly the last few paragrphs.


  2. The data are calculated a priori by a rather involved QM procedure. I believe it's basically about introducing the magnetic field perturbation as a perturbation Hamiltonian that's added to the regular Hamiltonian, although I have to admit that the exact details are still a black box for me. I will take a look at the SC post


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