Imperial College London

Henry Rzepa

Cavities promote reactions, and they can also trap the products of
reactions. Such (supramolecular) chemistry is used to provide models for
how enzymes work, but it also allows *un-natural* reactions to be
undertaken. A famous example is the preparation of P~4~ ([see blog post
here](http://www.ch.ic.ac.uk/rzepa/blog/?p=546){target="references"}),
an otherwise highly reactive species which, when trapped in the cavity
is now sufficiently protected from the ravages of oxygen for its X-ray
structure to be determined. A colleague recently alerted me to a
just-published article by Legrand, van der Lee and Barboiu (DOI:
[10.1126/science.1188002](http://dx.doi.org/10.1126/science.1188002){target="references"})
who report the use of cavities to trap and stabilize the notoriously
(self)reactive 1,3-dimethylcyclobutadiene (**3/4** in the scheme below).
Again sequestration by the host allowed an x-ray determination of  the
captured species!

::: {#attachment_2356 .wp-caption .aligncenter style="width: 457px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/08/scheme.jpg "scheme"){.size-full
.wp-image-2356 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2356" width="447"
height="278"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/08/scheme.jpg)

Scheme for production of 1,3-dimethylcyclobutadiene 3 and CO2.
:::

The colleague tells me he has himself already penned an article on the
topic and submitted this to a conventional journal. However, their rules
decree that whilst it is being refereed, I could not discuss the article
here, or indeed even name its author. Assuming his article is published,
[I will indeed reveal his
identity](http://www.ch.ic.ac.uk/rzepa/blog/?p=2828){target="_blank"},
so that he gets the credit he deserves! Meanwhile, I will concentrate in
this blog purely on two other aspects of this reaction which caught my
own eye after he brought the article to my attention.

The reaction involves imobilising a precursor **1** in a
crystalline calixarene network as shown above, and then *in situ*
photolysis to form the Dewar lactone **2**. Further photolysis then
results in extrusion of carbon dioxide and the formation of 1,3-dimethyl
cyclobutadiene **3** and
**[CO]{style="font-weight: normal;"}~[2]{style="font-weight: normal;"}~,**
both still trapped in the host crystals. Thus imobilised, here they both
apparently remain (at 175K) for long enough for their X-ray structure to
be determined. What attracted me to this chemistry was the potential of
this reaction as a nice example of a Diels Alder reaction occuring in a
cavity. The first example of such catalysis was reported by Endo, Koike,
Sawaki, Hayashida, Masuda, and Aoyama (DOI:
[10.1021/ja964198s](http://dx.doi.org/10.1021/ja964198s){target="references"})
and I have used this i[n my
lectures](http://www.ch.ic.ac.uk/local/organic/mod/mo_5.html#case5a){target="_blank"}
for many years. This latter example however illustrates the promotion of
a *cycloaddition*, which inside a cavity is accelerated by a factor of
\~10^5^, rather than of the reverse *cycloelimination*. I explain this
to students by invoking entropy. Normally, when two molecules react
together, there is an entropic penalty, which can add 8 or more kcal/mol
to the free energy of activation of a bimolecular reaction in the
absence of the cavity.

::: {#attachment_2360 .wp-caption .aligncenter style="width: 410px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/08/cbd.jpg "cbd"){.size-full
.wp-image-2360 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2360" width="400"
height="319"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/08/cbd.jpg)

Structure of entrapped 1,3-dimethylcyclobutadiene, obtained from the CIF
file provided via DOI: 10.1126/science.1188002
:::

By a strange coincidence, my name is also on a recently published
article (DOI:
[10.1021/ol9024259](http://dx.doi.org/10.1021/ol9024259){target="references"})
with other colleagues on the use of (Lewis) acid catalysts to accelerate
a type of reaction known as the
[Prins](http://en.wikipedia.org/wiki/Prins_reaction){target="references"}.
This involves the addition of an alkene to a carbonyl group. Now as it
happens, the reaction in the scheme above showing **4** → **2** happens
to combine these features; it is both a Diels-Alder cycloaddition and
also involves an alkene adding to a carbonyl compound! It is therefore
noteworthy that the claimed reaction **1** → **2** → **3** + CO~2~ is
done in the presence of a strong acid catalyst, the guanidinium cation
**5**, which is itself part of the structure of the calixarene-based
host. It is represented as X in the scheme above, and can also be
identified in the above 3D model *via* the light blue atoms.

There are however crucial differences between these two earlier examples
I quoted and the reaction of **2** → **3**; the latter is in fact a
**cycloelimination** and not a (cyclo)addition. In other words,
according to literature precedent, the guanidinium cation-based cavity
should act to accelerate the reverse cycloaddition **4** → **2** rather
than the forward cycloelimination. Since the isomerisation **3** → **4**
is thought to be fast, the question arises: how rapid is the reverse
reaction **4** → **2**? In particular, is it slow enough to allow X-ray
diffraction data to be collected for **3**/**4** over the necessary
period of 24 hours or more? Legrand, van der Lee and Barboiu do not
address this point in their article. Nor is there discussion there of
how the cavity and the acid catalyst might influence the position of the
equilbrium **2** → **3** + CO~2~.

This is where calculations can help. At the B3LYP/6-311G(d,p) level four
different models were selected.

1. Model **A** is a simple gas phase calculation for the singlet state,
 which reveals the free energy barrier for **4** → **2** is already
 quite modest for a Diels-Alder reaction (more typical values are
 \~22 kcal/mol), due no doubt to the instability/reactivity of the
 cyclobutadiene. However, at 175K, that would still be quite
 sufficient to prevent the reverse reaction from occurring to any
 extent over the period of X-ray data collection.
2. Model **B** adds a condensed phase (water) to the model. This serves
 in part to simulate the condensed crystal environment (which is
 pretty ionic being a tetra ion-pair). The barrier drops to 12.1
 kcal/mol.
3. Adding one guanidinium cation to both these models (**C** and **D**)
 which simulate the Prins conditions, drops the barrier to 8.3
 kcal/mol (model 4).
4. You can inspect details of any of the calculations by clicking on
 the digital repository entry (shown as ^dr^ in the table), where
 full data is available.

None of these models includes the entropic effects of full constraint in
a cavity (which I estimated above as capable of reducing the free energy
barrier for reaction by \~8 or more kcal/mol). If this correction is
applied to model **D**, it would reduce the barrier to \~0 kcal/mol! The
calculations also reveal that the reverse reaction **4** → **2** is
exothermic, and this exothermicity is enhanced by the acid catalyst
**5**. It would be further enhanced by reducing the entropy of reaction
by pre-organizing the reactants in the cavity. The tendency must
therefore be for **3/4** to revert to **2** on purely thermodyamic
grounds, and only the presence of a significant kinetic barrier would
allow them to exist as separate species. This barrier, as one might
infer from the calculations shown in the table below, may not be a large
one. Even a barrier of 8 kcal/mol might require cooling to significantly
lower than 175K to render the reaction slow on a \~24 hour timescale.

<table data-border="1">
<colgroup>
<col style="width: 25%" />
<col style="width: 25%" />
<col style="width: 25%" />
<col style="width: 25%" />
</colgroup>
<tbody>
<tr class="header">
<th>Model</th>
<th>ΔG‡4 → 2 
kcal/mol</th>
<th>ΔGreac 4 → 2</th>
<th>Singlet-triplet 
separation</th>
</tr>
&#10;<tr class="odd">
<td>A. Gas phase,X=none</td>
<td><a href="http://hdl.handle.net/10042/to-5049"
target="references">dr</a> ts 16.8 <a
href="http://hdl.handle.net/10042/to-5050"
target="references">dr</a></td>
<td>-3.5<a href="http://hdl.handle.net/10042/to-5051"
target="references">dr</a></td>
<td>+5.7 <a href="http://hdl.handle.net/10042/to-5074"
target="references">dr</a></td>
</tr>
<tr class="even">
<td>B. Continuum solvent (water),X=none</td>
<td><a href="http://hdl.handle.net/10042/to-5052"
target="references">dr</a> ts 12.1<a
href="http://hdl.handle.net/10042/to-5054"
target="references">dr</a></td>
<td>-6.0 <a href="http://hdl.handle.net/10042/to-5053"
target="references">dr</a></td>
<td>+7.7 <a href="http://hdl.handle.net/10042/to-5075"
target="references">dr</a></td>
</tr>
<tr class="odd">
<td>C. Gas phase,X=guanidinium+</td>
<td><a href="http://hdl.handle.net/10042/to-5056"
target="references">dr</a> ts 6.1 <a
href="http://hdl.handle.net/10042/to-5057"
target="references">dr</a></td>
<td>-19.5<a href="http://hdl.handle.net/10042/to-5055"
target="references">dr</a></td>
<td>+2.1<a href="http://hdl.handle.net/10042/to-5057"
target="references">dr</a></td>
</tr>
<tr class="even">
<td>D. Continuum solvent (water),X=guanidinium+</td>
<td><a href="http://hdl.handle.net/10042/to-5047"
target="references">dr</a> ts 8.3 <a
href="http://hdl.handle.net/10042/to-5046"
target="references">dr</a></td>
<td>-10.1 <a href="http://hdl.handle.net/10042/to-5048"
target="references">dr</a></td>
<td>+7.7 <a href="http://hdl.handle.net/10042/to-5076"
target="references">dr</a></td>
</tr>
</tbody>
</table>

So I end my own speculations here on the nature of the reaction reported
by Legrand, van der Lee and Barboiu by asking: are the products they
claim (1,3-dimethylcyclobutadiene and carbon dioxide) capable of
existing as separate species for long enough inside their cavity, even
at 175K, to allow for the collection of X-ray data for a structure
determination?

I tend to think probably not (? rather than !). But do decide for
yourselves.

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

Archived as
[http://www.webcitation.org/5rpkn2Z5S](http://www.webcitation.org/5rpkn2Z5S){target="_blank"}
on 08/08/2010. See also [this
post](http://www.ch.ic.ac.uk/rzepa/blog/?p=2594){target="_blank"}.

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

Cavities promote reactions, and they can also trap the products of reactions. Such (supramolecular) chemistry is used to provide models for how enzymes work, but it also allows

 un-natural

reactions to be undertaken.

Messaggi di Rogue Scholar

Reactions in supramolecular cavities – trapping a cyclobutadiene: ! or ?