Imperial College London

Henry Rzepa

Back in the days (1893) when few compounds were known, new ones could
end up being named after the discoverer. Thus Feist is known for the
compound bearing his name; the 2,3 carboxylic acid of
methylenecyclopropane (**1**, with Me replaced by CO~2~H). Compound
**1** itself nowadays is used to [calibrate chiroptical
calculations](http://comporgchem.com/blog/?p=2465){target="_blank"}\[cite\]10.1021/ct300359s\[/cite\],
which is what brought it to my attention. But about four decades ago,
and now largely forgotten, both **1** and the dicarboxylic acid were
famous for the following rearrangement that gives a mixture of **2** and
**3**\[cite\]10.1021/ja00747a019\[/cite\]. I thought I might here unpick
some of the wonderfully subtle stereochemical analysis that this little
molecule became subjected to.  
![methylene-cyclopropane](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/methylene-cyclopropane.svg){.aligncenter
.size-full .wp-image-10146 decoding="async"}

Feist's acid and its derivatives have attracted constant attention a
long while. The rearrangement shown above was identified in 1932, and by
1960 it was shown that **1** as a pure enantiomer gave products **2**
and **3** that retained optical activity (read about all of this
here\[cite\]10.1016/S0040-4020(01)92859-5\[/cite\]). By 1970 attention
had shifted to the absolute configurations of the molecules involved and
the mechanism of the reaction. Why? Woodward and Hoffmann had just put
pericyclic reactions on the map\[cite\]10.1002/anie.196907811\[/cite\],
and one of the examples they cited was this one. They identified the
reaction as a \[1,3\]sigmatropic rearrangement (the [red
bond]{style="color: #ff0000;"} breaks and the [blue
bond]{style="color: #0000ff;"} forms) and their new theory required the
configuration at carbon **1** to be inverted by the reaction, from (R)
to (S) as shown above. In order to verify this, von Doering (who had
been a student of Woodward's) subjected Feist's ester and its
rearrangement products to a series of chemical
transformations\[cite\]10.1002/anie.196907811\[/cite\] in order to
relate its absolute stereochemistry to that of known compounds.
Gajewski\[cite\]10.2012/ja00747a019\[/cite\] took over and with four
further chemical transformations, was able to assert that the
(S,S)-dimethyl enantiomer of **1** has an optical rotation of -59.4°.^‡^
The molecules **2** and **3** were subjected to a similar stereochemical
analysis, which finally revealed them to have (S) configuration at the
carbon labelled **1**, thus confirming the ***inversion of
configuration*** so confidently predicted by Woodward and Hoffmann. I
imagine Feist never imagined the molecule which came to bear his name
would be used as a confirmation of one of the pivotal 20th century
stereochemical theories of organic chemistry.

So what of the mechanism for this rearrangement? Well,
a ωB97XD/6-311G(d,p) calculation reveals the transition state as shown
below. The two dashed lines represent the red and blue bonds shown
schematically above, and these bond either break or form to the same
face of the three-carbon allyl fragment (suprafacially), but that carbon
**1** (pointed to by the blue arrow below) suffers an Sn2-like inversion
of configuration (= antarafacial) as proven by all that hard chemical
synthesis noted
above. ![methylene-cyclopropane](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/methylene-cyclopropane.jpg){.aligncenter
.wp-image-10154 loading="lazy" decoding="async" width="356"
height="315"}

The reaction is concerted, with a predicted barrier of around 50
kcal/mol. This is a little higher than the measured value of \~41
kcal/mol\[cite\]10.1021/ja00901a009\[/cite\]. This is taken to indicate
that the wavefunction has a contribution from an open-shell biradical
configuration (indeed it is unstable at the transition state, having a
lower energy triplet state) which would lower the barrier by 10-15
kcal/mol. The observation that the product has NOT lost optical activity
suggests that the mechanism cannot simply be that of an achiral
biradical, and that a "memory" of the starting stereochemical
configuration must be retained throughout the dynamic reaction
trajectory. Modelling such a process requires more sophisticated
(multi-configuration) techniques than the one I have illustrated here,
and quite probably a smattering of reaction dynamics thrown in. It goes
to show that quite innocent looking molecules can be devils to model
(both for their reaction dynamics **and** their optical activity!). 

|                                                                                                                                                                                                                                           |                                                                                                                                                                                              |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![methylenecyclopropane](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/methylenecyclopropane3.gif){.aligncenter .size-full .wp-image-10161 decoding="async" width="220"}-\[cite\]10.6084/m9.figshare.670632\[/cite\] | ![methylenecyclopropane](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/methylenecyclopropane.svg){.aligncenter .size-full .wp-image-10152 decoding="async" width="210"} |

Feist's acid itself reveals a profile for the computed rearrangement IRC
(ωB97XD/6-311G(d,p)/SCRF=water) that I have never seen as prominently
before, a veritable [table
top](http://en.wikipedia.org/wiki/Table_Mountain){target="_blank"} of a
mountain! This feature (and its reflection in the gradient norm) is a
nice example of a "hidden intermediate". In this case, it is a species
which may be either biradical or zwitterionic, and which sits atop the
mountain plateau. It can drop (bifurcate) off the mountain to form
either compound **2** or **3**, a process which must likely be best
studied by dynamics rather than purely as an intrinsic reaction
coordinates.

<table class="aligncenter" data-border="0" data-align="center">
<colgroup>
<col style="width: 50%" />
<col style="width: 50%" />
</colgroup>
<tbody>
<tr class="odd">
<td><div id="attachment_10164" class="wp-caption aligncenter"
style="width: 230px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/feist1.gif"
class="wp-image-10164" loading="lazy" decoding="async"
aria-describedby="caption-attachment-10164"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2013/04/acid.log;frame 91;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 10;animation mode loop;&#39;);"
width="220" height="182" alt="feist1" />
<p>Click for 3D</p>
</div>
<br />
<br />
[cite]10.6084/m9.figshare.674600[/cite]</td>
<td><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/feiste.svg"
class="aligncenter size-full wp-image-10166" decoding="async"
width="210" alt="feiste" /></td>
</tr>
<tr class="even">
<td colspan="2"> <img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/feistg.svg"
class="aligncenter size-full wp-image-10167" decoding="async"
width="320" alt="feistg" /></td>
</tr>
</tbody>
</table>

 

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

^‡^See [comment
here](http://comporgchem.com/blog/?p=2465){target="_blank"}.

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


Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (
<strong>
 1
</strong>
, with Me replaced by CO
<sub>
 2
</sub>
H). Compound
<strong>
 1
</strong>
itself nowadays is used to calibrate chiroptical calculations[cite]10.1021/ct300359s[/cite], which is what brought it to my attention.

Messaggi di Rogue Scholar

Feist’s acid. Stereochemistry galore.