Imperial College London

Henry Rzepa

  
Every introductory course or text on aromatic electrophilic substitution
contains an explanation along the lines of the resonance diagram shown
below. With an *o*/*p* directing group such as NH~2~, it is argued that
negative charge accumulates in those positions as a result of the
resonance structures shown.

::: {#attachment_112 .wp-caption .aligncenter style="width: 250px"}
![groups1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/groups1.jpg "groups1"){.aligncenter
.size-full .wp-image-112 loading="lazy" decoding="async"
aria-describedby="caption-attachment-112"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load \"wp-content/uploads/2009/04/ph-nh2.jvxl\";isosurface \"\";zoom 150;color isosurface blue;');"
width="240" height="267"}

MEP for PhNH2. Click for 3D.
:::

The opposite occurs for electron withdrawing groups. Shown below is a
group such as BR~2~, a somewhat unusual choice it has to be said (and
indeed rather un-represented in the literature as well).

::: {#attachment_113 .wp-caption .aligncenter style="width: 282px"}
![groups2](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/groups2.jpg "groups2"){.aligncenter
.size-full .wp-image-113 loading="lazy" decoding="async"
aria-describedby="caption-attachment-113"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load \"wp-content/uploads/2009/04/ph-bh2.jvxl\";isosurface \"\";zoom 150;color isosurface blue;');"
width="272" height="254"}

MEP for PhBH2. Click for 3D.
:::

But stick with me for a little while on this one, since we are now going
to pose the question: what the result of combining both groups onto the
same aryl ring, as below?

::: {#attachment_116 .wp-caption .aligncenter style="width: 275px"}
![mixed2](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/mixed2.jpg "mixed2"){.aligncenter
.size-full .wp-image-116 loading="lazy" decoding="async"
aria-describedby="caption-attachment-116"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load \"wp-content/uploads/2009/04/phbh2nh2a.jvxl\";isosurface \"\";zoom 150;color isosurface blue;');"
width="265" height="172"}

MEP for PhBH2NH2. Click for 3D.
:::

The conventional outcome, based on the resonance forms shown in the
first two diagrams, is that the two positions annotated with red text
are disfavoured, and the two positions labelled with green or orange
text are both favoured. Thus far, we are still in "exam question
territory". Reality however intrudes. When a similar combination of
electron withdrawing and donating groups is tried out in the lab, only
the green outcome is observed, and not the orange. So finally, the point
of this blog. Is there any other tool we can use to (correctly) predict
the outcome of this particular reaction?

One way of mapping where charge in a molecule accumulates or decreases
is a property known as the **molecular electrostatic potential** (see
1[0.1021/ja973105j](http://dx.doi.org/10.1021/ja973105j){target="_blank"}
and references cited there for details). Put simply, it measures how
attractive (blue) or repulsive (red) any region of the molecule is to a
proton placed at any point surrounding the molecule. Mapping these
regions produces so-called iso-surfaces, where the measure of repulsion
or attraction is the same everywhere on this surface.

So now, if you click on the first diagram, you will see this
[MEP](http://www.ch.ic.ac.uk/rzepa/talks/madrid/groups1.html){target="new"}.
Notice how it is blue close to the *o* or *p* positions, and does its
best to avoid the *m* position.

::: {#attachment_151 .wp-caption .aligncenter style="width: 281px"}
![Molecular electrostatic
potential](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/groups11.jpg "groups11"){.size-full
.wp-image-151 loading="lazy" decoding="async"
aria-describedby="caption-attachment-151" width="271" height="212"}

Molecular electrostatic potential
:::

Clicking on the second diagram will reveal the opposite.

::: {#attachment_154 .wp-caption .aligncenter style="width: 234px"}
![Molecular electrostatic
potential](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/groups21.jpg "groups21"){.size-full
.wp-image-154 loading="lazy" decoding="async"
aria-describedby="caption-attachment-154" width="224" height="140"}

Molecular electrostatic potential
:::

Thus far this simple picture is in perfect accord with the simple
resonance diagrams we started with. But the advantage of this MEP method
is that the effects of two (or indeed more) substituents can be properly
combined to give an overall effect. Thus in the [third
diagram](http://www.ch.ic.ac.uk/rzepa/talks/madrid/multiple2.html){target="new"},
you can now see that the blue accumulates only over the green-text
region, and not at all over the orange-text region!

::: {#attachment_156 .wp-caption .aligncenter style="width: 182px"}
![Molecular electrostatic
potential](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2009/04/groups3.jpg "groups3"){.size-full
.wp-image-156 loading="lazy" decoding="async"
aria-describedby="caption-attachment-156" width="172" height="220"}

Molecular electrostatic potential
:::

OK, one can derive a resonance structure in 5 seconds in an exam. One
can hardly compute a MEP under such conditions. But what this example
shows is that sometimes, quantum mechanics produces results which cannot
be simply reduced to memorable rules, but must be applied natively to
get the correct result.

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


Every introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an

 o

/

 p

directing group such as NH

 2

, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown. MEP for PhNH2. Click for 3D.The opposite occurs for electron withdrawing groups.

Rogue Scholar Beiträge

Aromatic electrophilic substitution: a different way of predicting regiospecificity