Imperial College London

Henry Rzepa

How does an anaesthetic work? Surprisingly, it is only
recently\[cite\]10.1038/nchembio.1340\[/cite\] that the possible binding
sites of the anaesthetic propofol (2,6-di-isopropylphenol) have been
identified using a technique known as photoaffinity
labelling.\[cite\]10.1016/j.bmc.2011.06.066\[/cite\] A propofol analogue
was constructed\[cite\]10.1038/nchembio.1340\[/cite\] by replacing one
of the isopropyl groups with a trifluoromethyl diazirine group (R=CF~3~,
X=Y=N below). Upon photolysis, this species looses nitrogen and forms a
carbene as a reactive species, which with further chemistry binds
covalently\[cite\]10.1016/j.bmc.2011.06.066\[/cite\] to adjacent amino
acids in the binding pocket.These modified segments could then be
analysed by mass spectrometry.\[cite\]10.1038/nchembio.1340\[/cite\] An
isomer of  diazirine
is [diazomethane](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6750){target="_blank"},
which is some 11 kcal/mol lower in free energy, but fortunately the
diazirene is preventing from thermally isomerising to this species by a
large kinetic barrier. That was the intro; now for a **connection**.^‡^
I recently attended a presentation on another medical topic, the
therapeutic uses of carbon monoxide.\[cite\]10.1038/nrd3228\[/cite\] In
higher concentrations it is notoriously lethal, but with appropriate
delivery it can be therapeutic. So, intertwingling, I asked myself what
the properties of the carbon monoxide isoelectronic analogue of a
diazirine might be (X=C, Y=O below). 

[![diazirene](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/diazirene.svg){.aligncenter
.size-full .wp-image-14577 decoding="async"
width="300"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/diazirene.svg)

Firstly, a search using Scifinder. More than 102 million molecules and
substances are reported there. Of course, that does not mean the
molecule actually exists, since many structures are only known by
calculation! But I could not find the CO analogue using a sub-structure
search. So this simple isoelectronic analogue of a very well-known
molecule type is not apparently well-known then (although I feel sure
that a theoretical chemist must have calculated it at some stage,^†^
even if the results were not reported and abstracted by CAS). Here is a
ωB97XD/6-311G(d,p)/SCRF=nitromethane set of calculations (kcal/mol).

|          |                                          |                                          |                                         |                                         |
|----------|------------------------------------------|------------------------------------------|-----------------------------------------|-----------------------------------------|
| Species  | ΔΔG~298~ ring                            | ΔΔG~298~ linear                          | ΔG^†^ XY extrusion                      | ΔG^†^ ring opening                      |
| X=Y=N    | 0.0\[cite\]10.14469/ch/191529\[/cite\]   | -11.0\[cite\]10.14469/ch/191530\[/cite\] | 36.1\[cite\]10.14469/ch/191534\[/cite\] | ---                                     |
| X=C, Y=O | 0.0\[cite\]10.14469/ch/191531\[/cite\]   | -63.3\[cite\]10.14469/ch/191535\[/cite\] | 27.3\[cite\]10.14469/ch/191532\[/cite\] | 46.8\[cite\]10.14469/ch/191533\[/cite\] |

We learn the following:

1.  The CO analogue is far less stable as a ring than the NN equivalent,
    but it is a clear-cut minimum in the energy surface.
2.  In the absence of any other conditions (for example protons), the
    free energy barrier for extruding CO is actually quite high, being
    only a little lower than the diazirine itself. The latter is
    thermally reasonably stable and not a fragile molecule at all. At
    face value therefore if made, such a cyclo-oxenium ylid might have a
    long enough "shelf life" to be detectable or trappable, certainly at
    lower temperatures. 
3.  It shows an even higher barrier to ring opening to form the far more
    stable ketene. This barrier is high enough that this reaction
    probably involves *e.g.* biradicals or other pathways.

[![ro-co1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ro-co1.gif){.aligncenter
.size-full .wp-image-14581 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ro-co1.gif)

[![ro-co](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ro-co.svg){.aligncenter
.size-full .wp-image-14582 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ro-co.svg)

[![ex-co1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ex-co1.gif){.aligncenter
.size-full .wp-image-14583 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ex-co1.gif)

[![ex-co](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ex-co.svg){.aligncenter
.size-full .wp-image-14585
decoding="async"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/09/ex-co.svg)

The question arises how such a CO analogue of diazirines might be made.
The very high relative energy does tend to suggest it might have to be a
photochemical approach. This would be a challenge, given that
photochemistry is also likely to promote CO extrusion. Most likely this
species is destined to join the (increasing) collection of molecules
known to science only by their computed properties! 

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^‡^Such connectedness in human knowledge has been termed
[intertwingularity](https://en.wikipedia.org/wiki/Intertwingularity){target="_blank"} by
Ted Nelson.

^†^Scifinder by and large only abstracts articles published in journals,
along with some of the data found there. Most calculations never make it
to such articles. The newly topical area of *Research Data Management*
strives to put in place an infrastructure that addresses such
issues.\[cite\]10.14469/hpc/143\[/cite\]

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Messaggi di Rogue Scholar

Isoelectronic games: the CO analogue of diazirines as an intriguing species?