Imperial College London

Henry Rzepa

A **scalemic** molecule is the term used by
[Eliel](http://www.uottawa.ca/publications/interscientia/inter.4/eliel/eliel.html){target="_blank"}
to describe any non-racemic chiral compound. Synthetic chemists imply it
when they describe a synthetic product with an observable enantiomeric
excess or **ee** (which can range from close to 0% to almost 100%).
There are two cheminformatics questions of interest to me:

1.  How many non-trivial scalemic molecules have been reported in the
    literature (let's assume their **ee** is significantly greater than
    0%)?
    - The distribution function for the **ee** of these molecules would
      be most interesting!
2.  Of those, how many have the absolute configuration of the
    predominant enantiomer established with high confidence?
    - Or, to put this another way, how many may prove to be
      mis-assigned?

Note the careful qualification in the above questions. Thus by
non-trivial, I mean compounds whose scalemic attributes persist in
solution for a chemically useful duration. That could be taken to mean
configurationally stable chiral molecules, rather than those that might
be conformationally chiral (an example of a trivial scalemic molecule
would be *e.g.* the twist-boat conformation of cyclohexane, which having
D~2~ symmetry is dissymetric, but which would only retain its scalemic
property for a trivially short timescale).

What are boundary values? These are some:

- As I write this, CAS records 61,257,703 chemical substances. Needless
  to say (unless I missed it), the answer to my first question is not to
  be found there.
- Beilstein (Reaxys) records 1,126,995 compounds as having one or more
  reported chiroptical properties (which is the most direct way of
  establishing a molecule is scalemic, although strictly, having say an
  optical rotation of 0° does not necessarily mean the molecule is not
  scalemic). We have no way of knowing how many molecules are scalemic
  for which no chiroptical measurement has been made (but one would hope
  its a small proportion). Perhaps that is a good answer to question
  **1**?
  - of which 1,097,094 relate to optical rotatory power, 17,515 to
    optical rotatory dispersion and 62,248 to electronic circular
    dichroism.
  - it is more difficult to answer how many of these 1,126,995
    substances have a firmly established absolute configuration.
    Measuring a chiroptical property *per se* does NOT in itself
    establish the absolute configuration. Doing so is a fascinating
    exercise in sequential logical argument, and how one does it has
    changed quite a lot over time. And what might I mean with *high
    confidence*? An older assignment (made say \> 40 years ago) might be
    less confident than one established in 2011 (fortunately, we can
    probably trust the absolute configurations of the amino acids!). A
    bit of a can of worms, nevertheless. But it interests me because it
    is a good example of what the **semantic web** is supposed to be all
    about.
- The Cambridge crystallographic database reports 560,307 entries, of
  which 72,340 are in chiral space groups (in which a chiral molecule
  can crystallise) and exhibit no disorder or other errors. We do not
  know how many of these are non-trivial, since all manner of small (and
  low energy) distortions can create a chiral species (in the solid
  state), but which would not persist  for a chemically useful duration
  in solution (*i.e.* it might for example immediately racemize and
  become non-scalemic).
- The [Flack
  parameter](http://dx.doi.org/10.1107/S0108767383001762){target="_blank"}
  has been used since [1983](%2010.1002/chir.20473){target="_blank"} for
  enantiomorph estimation (a value of \~≤ 0.10(10) would be considered
  meaningful). This could in principle provide an answer of known
  confidence to my question **2** above (but would not address the issue
  of non-triviality).
  - The challenge now is to quantify how many compounds have a
    meaningful reported Flack parameter (presumably a sub-set of
    72,340?)

Let me declare one personal interest. Over the last four years or so, we
have been asked to confirm the absolute configuration of around eight
scalemic molecules. After a detailed study, we concluded three were
mis-assigned. Now this in no way implies anything about what the answer
to question **2** above might be! But it does make one think!

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


A
<strong>
 scalemic
</strong>
molecule is the term used by Eliel to describe any non-racemic chiral compound.

Messaggi di Rogue Scholar

Scalemic molecules: a cheminformatics challenge!