Imperial College London

Henry Rzepa

Members of the chemical FAIR data community have just met in Orlando
(with help from the [NSF, the American National Science
Foundation](https://iupac.org/event/fair-publishing-guidelines-for-spectral-data-and-chemical-structures/){target="_blank"
rel="noopener noreferrer"}) to discuss how such data is progressing in
chemistry. There are a lot of themes converging at the moment. Thus this
article\[cite\]10.1039/c7np00064b\[/cite\] extolls the virtues of having
raw NMR data available in natural product research, to which we added
that such raw data should also be made **FAIR** (Findable, Accessible,
Interoperable and Reusable) by virtue of adding rich metadata and then
properly registering it so that it can be searched. These themes are
combined in another article which made a recent
appearance.\[cite\]10.1021/acsomega.8b03005\[/cite\]

One of the speakers made a very persuasive case based in part on *e.g.*
the following three molecules which are discussed in the first
article\[cite\]10.1039/c7np00064b\[/cite\] (the compound numbers are
taken from there). The question was posed at our meeting: ***why did the
referees not query these structures***? And the answer in part is to
provide referees with access to the full/primary/raw NMR data (which
almost invariably they currently do not have) to help them check on the
peaks, the purity and indeed the assignments. I am sure tools that do
this automatically from such supplied data by machines on a routine
basis do exist in industry (and which is something FAIR is designed to
enable). Perhaps there are open source versions available?

<table data-border="1">
<colgroup>
<col style="width: 33%" />
<col style="width: 33%" />
<col style="width: 33%" />
</colgroup>
<tbody>
<tr class="header">
<th>17</th>
<th>18</th>
<th>19</th>
</tr>
&#10;<tr class="odd">
<td><a
href="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/17.svg"><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/17.svg"
class="aligncenter size-large wp-image-20602" decoding="async"
width="100" /></a><br />
 </td>
<td><a
href="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/18.svg"><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/18.svg"
class="aligncenter size-large wp-image-20603" decoding="async"
width="100" /></a></td>
<td><a
href="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/19.svg"><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/19.svg"
class="aligncenter size-large wp-image-20604" decoding="async"
width="250" /></a></td>
</tr>
<tr class="even">
<td>328[cite]10.1002/ejoc.201301308[/cite]</td>
<td>348</td>
<td>713</td>
</tr>
</tbody>
</table>

Here I suggest a particularly simple and rapid "reality check" which I
occasionally use myself. This is to compute the *steric energy* of the
molecule using molecular mechanics. The mechanics method is basically a
summation of simple terms such as the bond length, bond angle, torsion
angle, a term which models non bonded repulsions, dispersion attractions
and electrostatic contributions. The first three are close to zero for
an unstrained molecule (by definition). The last three terms can be
negative or positive, but unless the molecule is protein sized, they
also do not depart far from zero. A suitable free tool that packages all
this up is [Avogadro](https://avogadro.cc).

The procedure is as follows

1.  Start from the Chemdraw representation of the molecule. If the
    publishing authors have been FAIR, you might be able to acquire that
    from their deposited data. Otherwise, redraw it yourself and save as
    *e.g.* a molfile or Chemdraw .cdxml file.
2.  Drop into Avogadro, which will build a 3D model for you using
    stereochemical information present in the Chemdraw or Molfile.
3.  In the ** E** tool (at the top on the left of the Avogadro menu)
    select *e.g.* the MMFF94 force field. This is a good one to use for
    "organic" molecules for which the total steric energy for "normal"
    molecules is likely to be \< 200 kJ. Calculate that for your system;
    this normally takes less than one minute to complete. The values
    obtained for the three above are shown in the table. All three are
    well over 200 kJ/mol, which should set alarm bells ringing.
4.  A "more reasonable" structure for **17** is shown below. This has a
    steric energy of 152 kJ/mol, some 176 kJ/mol lower than the original
    structure. This does not of itself "prove" this alternative, but it
    is a starting point for showing it might be
    correct.[![](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/17-correct1.svg){.aligncenter
    .size-large .wp-image-20615 decoding="async"
    width="150"}](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/17-correct1.svg)Of
    course mis-assigned but otherwise reasonable structures are unlikely
    to be revealed by the steric energy test. But impossible ones will
    probably always be flagged as such using this procedure. 

------------------------------------------------------------------------

**Postscript**: Hot on the heels of writing this, the molecule
**Populusone** came to my
attention.\[cite\]10.1021/acs.orglett.9b00423\[/cite\] On first sight,
it seems to have some of the attributes of an "impossible molecule"
(click on diagram below for 3D coordinates).  
![](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2019/04/liukaixin_384.svg){.aligncenter
.size-full .wp-image-20631 decoding="async"
onclick="jmolApplet([450,450],'load wp-content/uploads/2019/04/Popusulin.mol;spin 3;','c2');"
width="300"}  
However, it has been fully characterised by x-ray analysis! The steric
energy using the method above comes out at 384 kJ/mol, which in the
region of impossibility! This can be decomposed into the following
components: bond stretch 30, bend 51, torsion 32, van der Waals
(including repulsions) 177, electrostatics 87 (+ some minor cross
terms). These are fairly evenly distributed, with internal steric
repulsions clearly the largest contributor. The C=C double bond is
hardly distorted however, which is in its favour. Clearly a natural
product can indeed load up the unfavourable interactions, and this one
must be close to the record of the most intrinsically unstable natural
product known!

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


Members of the chemical FAIR data community have just met in Orlando (with help from the NSF, the American National Science Foundation) to discuss how such data is progressing in chemistry. There are a lot of themes converging at the moment.

Messaggi di Rogue Scholar

Impossible molecules.