Imperial College London

Henry Rzepa

Peter Murray-Rust in his blog asks for examples of the [Scientific
Semantic
Web](http://wwmm.ch.cam.ac.uk/blogs/murrayrust/?p=2253b){target="_blank"},
a topic we have both been banging on about for ten years or more (DOI:
[10.1021/ci000406v](http://dx.doi.org/10.1021/ci000406v){target="_blank"}).
What we are seeking of course is an example of how scientific
connections have been made using inference logic from semantically rich
statements to be found on the Web (ideally connections that might not
have previously been spotted by humans, and lie overlooked and unloved
in the scientific literature). Its a tough cookie, and I look forward to
the examples that Peter identifies. Meanwhile, I thought I might share
here a semantically rich molecule. OK, I identified this as such not by
using the Web, but as someone who is in the process of delivering an
undergraduate lecture course on the topic of [conformational
analysis](http://www.ch.ic.ac.uk/local/organic/conf/){target="_blank"}.
This course takes the form of presenting a set of rules or principles
which relate to the conformations of molecules, and which themselves
derive from quantum mechanics, and then illustrating them with selected
annotated examples. To do this, a great many semantic connections have
to be made, and in the current state of play, only a human can really
hope to make most of these. We really look to the semantic web as it
currently is to perhaps spot a few connections that might have been
overlooked in this process. So, below is a molecule, and I have made a
few semantic connections for it (but have not actually fully formalised
them in this blog; that is a different topic I might return to at some
time). I feel in my bones that more connections could be made, and offer
the molecule here as the fuse!

::: {#attachment_1939 .wp-caption .aligncenter style="width: 354px"}
![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/05/DULSAE.jpg "DULSAE"){.size-full
.wp-image-1939 loading="lazy" decoding="async"
aria-describedby="caption-attachment-1939"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('black');jmolApplet([450,450],'load wp-content/uploads/2010/05/DULSAE10.cif;measure 30 35;measure 22 26;measure 31 29;');"
width="344" height="126"}

Two chair conformations of the molecule DULSAE. Click here for 3D. Note
the (attractive) short H\...H contacts.
:::

To list all the likely semantics that a chemist would perceive in the
graphic above would take far too long (by the time one would have
finished, a text book would have been written). So here is a very very
short summary in the context of conformational analysis.

1.  The molecule has a six membered ring as its backbone
2.  which can adopt two possible chair conformations
3.  which can interconvert by exchanging the axial and equatorial group
    pair for each of the four carbon atoms in the ring.
4.  An organic chemist will immediately notice a very unusual group,
    Fe(CO)~2~Cp, which itself is a semantic goldmine,
5.  but for the purposes here we will regard merely as a C-Fe bond!

The (semantic) question to be posed is "**which of the two conformations
shown above is the most stable**"? That too of course has an abundance
of implicit semantics, but most human chemists will probably know that
this refers to asking which of the two geometries represents the lowest
thermodynamic free energy (and we leave aside the issue of what medium
the molecule is in, i.e. solid, solution or gas). A far trickier
question is "why"?

So to (some interim) answers. Well, a ωB97XD/6-311G(d) calculation (wow,
think of what is implied in that concise notation) predicts conformation
(a) to be more stable by 2.3 kcal/mol (2.1 in ΔG, see DOI:
[10042/to-4911](http://hdl.handle.net/10042/to-4911)). Now to the why.
What connections would someone well versed in conformation analysis
spot?

1.  The molecule has two methyl groups on adjacent atoms. They may
    prefer to be di-axial rather than di-equatorial to avoid excessive
    steric repulsions (whatever we mean by that!). That might prefer
    (b).
2.  The molecule has one carbon with both a cyano and an ether linkage.
    Well, that is susceptible to an anomeric effect (although, as [I
    pointed out in an earlier post
    here](http://www.ch.ic.ac.uk/rzepa/blog/?p=745){target="_blank"},
    this connection has in fact often NOT been made in the literature).
    Only in conformation (a) is one of the oxygen lone pairs aligned
    anti-periplanar to the axis of the C-CN bond. The reasons why this
    is important are outlined in my [Lecture
    course](http://www.ch.ic.ac.uk/local/organic/conf/){target="_blank"}.
3.  Having spotted the last, the human might ask whether there is any
    possibility of an anomeric effect between an oxygen lone pair and
    the axis of the C-Fe bond? Well, I rather think that not a single
    human ever has asked that question! (I cannot know that of course,
    and perhaps someone has speculated upon this in the literature; this
    is where a full semantic web would help. That question could be
    posed of it! The reason  I suspect the connection might not have
    been made is that the anomeric effect is the domain of the organic
    chemistry, and  C-Fe bonds are those of the organometallic chemist.
    They do tend to see the chemical world rather differently, these two
    groups of chemists). If there was such an effect, it would favour
    (a).
4.  Then we have an [X-C-C-Y
    motif](http://www.ch.ic.ac.uk/rzepa/blog/?p=1887){target="_blank"}.
    Depending on the nature of X and Y, the molecule might actually
    prefer a gauche conformation, i.e the dihedral angle XCCY would be
    around 60°. There are several such motifs one can detect; X=Y=O
    (twice). It might be that other permutations such as X=CN,
    Y=Fe(CO)~2~Cp, favour anti-periplanar. There are other permutations
    whose orientational preference may not even be recorded (in text
    books). Suddenly its gotten complicated!
5.  There are a number of [short (\~2.4Å) H...H
    contacts](http://www.ch.ic.ac.uk/rzepa/blog/?p=1856){target="_blank"}
6.  We are starting to understand that to unravel the conformation of
    this molecule, one may have to identify quite a number of different
    "rules", and then to quantify each, and add up the numbers to get
    the final result. That energy of 2.3 kcal/mol may be composed of the
    result of applying quite a number of different rules. Hence the
    title of this post, a semantically rich molecule!

Well, I will leave it here for this post, without giving answers to the
six points listed above, or really answering my main question posed
above. That would make the post too complex (but I will follow this
up!). I do want to end by planting the idea that answering this question
involves making a great many chemical connections about the properties
of this molecule, and then identifying quantitative ways (algorithms) in
which an answer can be formulated. The molecule above is presented as a
challenge for the Semantic Web to address!

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


Peter Murray-Rust in his blog asks for examples of the Scientific Semantic Web, a topic we have both been banging on about for ten years or more (DOI: 10.1021/ci000406v). What we are seeking of course is an example of how scientific connections have been made using inference logic from semantically rich statements to be found on the Web (ideally connections that might not have previously been spotted by humans, and lie overlooked and unloved in

Rogue Scholar Beiträge

Semantically rich molecules