Imperial College London

Henry Rzepa

Functionalisation of a (hetero)aromatic ring by selectively (directedly)
removing protons using the metal lithium is a relative mechanistic
newcomer, compared to the pantheon of knowledge on [aromatic
electrophilic
substitution](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9706 "Kinetic vs Thermodynamic control. Subversive thoughts for electrophilic substitution of Indole."){target="_blank"}.
Investigating the mechanism using quantum calculations poses some
interesting challenges, ones I have not previously discussed on this
blog.

![Li](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li.svg){.aligncenter
.size-full .wp-image-9779 decoding="async"}

My model will be the system above, based on the pyridine ring, and also
carrying a directing group (R=Me, DG = O^--^). The reagent used to
remove the hydrogen and to substitute it (with a carbon-metal bond) is
an alkyl lithium. The arrow pushing I have shown is speculative, since
at this stage we have no idea if it really is such a pericyclic process.
Indeed things are about to get complicated when we find out that the
structure of the electron deficient lithium alkyls is much more complex
than one might imagine.

Fortunately, crystal structures are available. Let me start with n-butyl
lithium, a very commonly used
reagent\[cite\]10.1002/anie.199305801\[/cite\]. This forms a complex
cluster of six lithiums, in which each metal is surrounded by three
CH~2~^--^ terminii of the n-butyl anion, and *vice-versa*,
each  CH~2~^--^ group is in contact with three lithium atoms (making the
carbanionic carbon in effect
[hexa-coordinate](http://www.ch.imperial.ac.uk/rzepa/blog/?p=2469){target="_blank"}).

::: {#attachment_9782 .wp-caption .aligncenter style="width: 254px"}
![SUHBEC. CLICK FOR
3D.](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/SUHBEC.jpg){.wp-image-9782
loading="lazy" decoding="async"
aria-describedby="caption-attachment-9782"
onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/03/SUHBEC.mol;');"
width="244" height="227"}

SUHBEC. CLICK FOR 3D.
:::

Another frequently used lithium alkyl is the t-butyl derivative, which
has a different tetrameric motif, again with each Me~3~C^--^ coordinated
to three Li atoms (making this carbon again hexa-coordinate).

::: {#attachment_9788 .wp-caption .aligncenter style="width: 256px"}
![SUHBIG. Click for
3D.](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/SUHBIG.jpg){.wp-image-9788
loading="lazy" decoding="async"
aria-describedby="caption-attachment-9788"
onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/03/SUHBIG.mol2;');"
width="246" height="214"}

SUHBIG. Click for 3D.
:::

The interesting issue now is whether these metal alkyls react in these
oligomeric forms or whether they are in equilibrium with a reduced
monomeric form that constitutes the reactive species. With n-butyl
lithium, it is possible to try to achieve this chemically by adding
tetramethylethylenediamine. As you can see from the structure below,
this strategy can be only partially successful; in this instance
the  CH~2~^--^  coordination is reduced from three Li atoms to
two\[cite\]10.1021/ja00057a050\[/cite\]. With t-butyl lithium, this
strategy reduces the structure to a true
monomer\[cite\]10.1021/ja8058205\[/cite\], the Me~3~C^--^ now being just
4-coordinate.

<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_9792" class="wp-caption aligncenter"
style="width: 217px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/WAFJAO.jpg"
class="wp-image-9792" loading="lazy" decoding="async"
aria-describedby="caption-attachment-9792"
onclick="jmolInitialize(&#39;../Jmol/&#39;,&#39;JmolAppletSigned.jar&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2013/03/WAFJAO.mol2;&#39;);"
width="207" height="228" alt="WAFJAO. Click for 3D." />
<p>WAFJAO. Click for 3D.</p>
</div></td>
<td><div id="attachment_9794" class="wp-caption aligncenter"
style="width: 232px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/LOKTAH.jpg"
class="wp-image-9794" loading="lazy" decoding="async"
aria-describedby="caption-attachment-9794"
onclick="jmolInitialize(&#39;../Jmol/&#39;,&#39;JmolAppletSigned.jar&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2013/03/LOKTAH.mol2;&#39;);"
width="222" height="212" alt="LOKTAH. Click for 3D." />
<p>LOKTAH. Click for 3D.</p>
</div></td>
</tr>
</tbody>
</table>

These systems are all pretty large to investigate using modelling, and
so I will start the process by reducing the alkyl lithium model down to
just a monomeric CH~3~Li molecule, placing it and pyridine-N-oxide into
a continuum solvent cavity (ωB97XD/6-311G(d,p)/SCRF=benzene) and seeing
what happens\[cite\]10.6084/m9.figshare.651068\[/cite\]. You can see it
is both facile and a concerted process, corresponding pretty much to the
arrow pushing illustrated at the top of this post.

|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![Li1a](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li1a.gif){.aligncenter .size-full .wp-image-9799 decoding="async" onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/03/Li1.log;frame 23;connect (atomno=6) (atomno=1) PARTIAL;connect (atomno=6) (atomno=13) PARTIAL;connect (atomno=12) (atomno=17) PARTIAL;connect (atomno=17) (atomno=13) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 20;animation mode loop;');" width="220"} |  ![Li1a](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li1a.svg){.aligncenter .size-full .wp-image-9800 decoding="async" width="220"} |

But wait, where have we seen an aromatic substitution reaction which
does exactly this in a single concerted step, first remove a proton and
then replace it with an electrophile? This was in fact revealed in the
IRC for [electrophilic substitution of indole in the
1-position](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9706){target="_blank"}!
Of course, there is a difference. With indole, we had pseudo-inversion
at the nitrogen centre (a pseudo-Sn2 reaction if you will), whereas here
it is pseudo-retention at the 2-carbon.

Is this model robust? Let us try a dimeric (MeLi)~2~ model coordinated
to one pyridine-N-oxide. The
IRC\[cite\]10.6084/m9.figshare.651764\[/cite\] is very similar, but the
initial barrier to proton transfer is lower.

|                                                                                                                                                         |                                                                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![Li2](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li2.gif){.aligncenter .size-full .wp-image-9803 decoding="async" width="220"} | ![Li2](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li2.svg){.aligncenter .size-full .wp-image-9805 decoding="async" width="220"} |

Next, we have a model in which two molecules of pyridine-N-oxide (PNO)
aggregate around two molecules of MeLi. This model is starting to
resemble the tetramethylethylenediamine partially de-aggregated n-butyl
lithium structure shown as WAFJAO above. The basic
features\[cite\]http://doi.org/10042/24399\[/cite\] of the process
remain intact, including the small barrier.

|                                                                                                                                                                            |                                                                                                                                                           |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![Li2d](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li2d.gif){.aligncenter .wp-image-9820 loading="lazy" decoding="async" width="236" height="181"} | ![Li2d](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li2d.svg){.aligncenter .size-full .wp-image-9821 decoding="async" width="220"} |

Finally, I go back to the simple model, but with the directing group
(DG) removed to give just pyridine. The
profile\[cite\]10.6084/m9.figshare.653672\[/cite\] is the same, but the
barrier is much larger. So perhaps both aggregation and coordination to
a directing group help accelerate the reaction?

|                                                                                                                                                |                                                                                                                                                           |
|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![Li0a](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li0a.gif){.aligncenter .wp-image-9832 decoding="async" width="220"} | ![Li0a](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/Li0a.svg){.aligncenter .size-full .wp-image-9831 decoding="async" width="220"} |

So two reaction types, not normally associated with each other, turn out
to have some intriguing similarities and an interesting difference.

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


Functionalisation of a (hetero)aromatic ring by selectively (directedly) removing protons using the metal lithium is a relative mechanistic newcomer, compared to the pantheon of knowledge on aromatic electrophilic substitution. Investigating the mechanism using quantum calculations poses some interesting challenges, ones I have not previously discussed on this blog.

Rogue Scholar Beiträge

Lithiation of heteroaromatic rings: analogy to electrophilic substitution?