Imperial College London

Henry Rzepa

Stereo-induction is, lets face it, a [subtle
phenomenon](http://www.ch.ic.ac.uk/rzepa/talks/hofmann/){target="_blank"}.
The ratio of two stereoisomers formed in a reaction can be detected very
accurately by experiment, and when converted to a free energy difference
using ΔG = -RT Ln K, this can amount to quite a small value (between 0.5
-- 1.5 kcal/mol). Can modelling reproduce effects originating from such
small energy differences? Well one system that has been argued about now
for several decades is shown below as **1**.

::: {#attachment_2121 .wp-caption .aligncenter style="width: 411px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene.jpg "Stereoinduction: syn or anti?"){.size-full
.wp-image-2121 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2121" width="401"
height="148"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene.jpg)

Norbornene systems
:::

[Way back in
1992](http://dx.doi.org/10.1039/C39920000998){target="_blank"}, we
thought that the explanation for attack by an electrophile on the alkene
from the *syn* face was electrostatic (although it did depend on the
nature of the electropile; thus we concluded that attack by Hg(OH)~2~
was electrostatic, but by BH~3~ was orbital controlled). Recently, a
different explanation has emerged, relating to how the fundamental
normal vibrational modes of the molecule interact with the transition
normal mode for the reaction. A [new example of
this](http://dx.doi.org/10.1038/nchem.577){target="_blank"}, relating to
reaction of the isomeric **2** with a peracid has recently been
discussed on [Steve Bachrach's
blog](http://comporgchem.com/blog/?p=977){target="_blank"}. Here, the
peroxide of the peracid is thought to act as an electrophile (although
one must bear in mind that it does bear two electron lone pairs!). The
conclusion was pretty clear cut; the experimental preference for *syn*
(92%) over the *anti* isomer (8%, ΔΔG = 1.4 kcal/mol) was NOT due to
electrostatic effects, but due to distorsional asymmetry in the
vibrational mode that couples/forms the transition state mode.

I could not resist revisiting this system. As in 1992, a molecular
electrostatic potential was calculated for **2**. The method used was
wB97XD/aug-cc-pvdz, and if you want the archive of this calculation to
evaluate it yourself, [see
here](http://hdl.handle.net/10042/to-4996){target="_blank"}).

::: {#attachment_2122 .wp-caption .aligncenter style="width: 273px"}
![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene-0.031.jpg "Electrostatic potential"){.size-full
.wp-image-2122 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2122"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2010/07/norbornene_0.029.jvxl;isosurface \"\" translucent;zoom 60;spin 3;');"
width="263" height="263"}

MEP for 2. Click on diagram for 3D.
:::

A very clear electrostatic bias for *syn* attack emerges (orange =
attractive to a proton=electrophile). This electrostatic picture is not
directly related to any distortional asymmetry, although of course both
could arise from the same electronic factors. They may indeed be
different manifestations of the same underlying nature of the
wavefunction. But I would claim here that to make the clear statement
that electrostatic effects are **NOT** responsible for the
discrimination in this reaction is perhaps too simplistic (electrostatic
potentials were not reported in the original article). The control
experiment is **3**, which is known to be far less selective. The
calculated electrostatic potential likewise shows much less
discrimination.

::: {#attachment_2136 .wp-caption .aligncenter style="width: 231px"}
![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene4-0.029.jpg "The norbornene with a four-membered ring"){.size-full
.wp-image-2136 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2136"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2010/07/norbornene4_0.029.jvxl;isosurface \"\" translucent;zoom 60;spin 3;');"
width="221" height="239"}

The norbornene with a four-membered ring
:::

Is there another take on **2**? Well, how about an NBO (natural bond
order) analysis? The interaction energy between the filled C1-C2 orbital
and the antibonding C15-C16 π\* bond is 3.24. This could be regarded as
pushing electrons into the anti-periplanar *syn* face of the alkene. The
corresponding C2-C9/C15-C16 interaction resulting in an
*anti*-preference is less at 2.55 kcal/mol. This effect arises because
the C1-C2 bond (localised as an NBO) is a better donor (E=-17.8eV) than
C2-C9 (E=-18.1eV). Because C2 is common to both, it must be the
difference between C1 and C9 (i.e. the hybridization of each). Perhaps
it's an orbital effect after all?

::: {#attachment_2124 .wp-caption .aligncenter style="width: 304px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene-0.029.jpg "Norbornene electrostatic potential"){.size-full
.wp-image-2124 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2124" width="294"
height="294"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/07/norbornene-0.029.jpg)

Norbornene electrostatic potential
:::

I would conclude by saying that it can be ferociously difficult to
identify the fundamental origins of stereo-induction. But I leave the
argument in the hands of the reader now. What do you think?

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


Stereo-induction is, lets face it, a subtle phenomenon. The ratio of two stereoisomers formed in a reaction can be detected very accurately by experiment, and when converted to a free energy difference using ΔG = -RT Ln K, this can amount to quite a small value (between 0.5 – 1.5 kcal/mol). Can modelling reproduce effects originating from such small energy differences?

Messaggi di Rogue Scholar

The mysteries of stereoinduction.