Imperial College London

Henry Rzepa

In answering tutorial problems, students often need skills in deciding
how much time to spend on explaining what does **not** happen, as well
as what does. Here I explore alternatives to the mechanism outlined in
the [previous
post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=14902){target="_blank"}
to see what computation has to say about what does (or might) not
happen.

[![TD](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/TD1.svg){.aligncenter
.size-full .wp-image-14946 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/TD1.svg)

I start with posing the question *what does the chloride counter-ion
do*? If you are aware of the literature on computational reaction
mechanisms, you may note that where ionic species are involved, one of
the ions is often excluded from the calculations. Here for example, the
pertinent reacting species is a diazonium cation, but the anion would
likely not be mentioned, and the calculation would be performed as a
charged cation (the physically unrealistic charge=1 in the input file!).
This is because of an awkward difficulty with ion-pairs. There is no
formal bond between the two charged fragments (unless a zwitterion) and
so it is not entirely obvious quite where to place the counter-ion. In
the diagram above, position **1** is where it was in my first
exploration, but with knowledge that it might form a hydrogen bond to an
acidic hydrogen, one could also perhaps place it into positions **2**
or **3**. In **2**, as shown by the blue arrows and product above, an
entirely different reaction occurs known as the ***Grob
fragmentation***.\[cite\]10.1002/hlca.19550380306\[/cite\] In fact as a
di-carbonyl compound, it can then participate in an acid-catalysed aldol
condensation and this can lead to the same product as the
original Tiffeneau-Demjanov rearrangement, albeit with loss of
stereochemical integrity. So it might be worth effort in explaining
whether this alternative is likely (in other words how robust the likely
stereochemical integrity of the product is).

|        |                         |                  |                                     |
|--------|-------------------------|------------------|-------------------------------------|
| System | Relative TS free energy | TS Dipole moment | DataDOI                             |
| 1      | 0.0                     | 17.7             | \[cite\]10.14469/ch/191653\[/cite\] |
| 2      | 1.4                     | 24.2             | \[cite\]10.14469/ch/191654\[/cite\] |
| 3      | 3.7                     | 29.3             | \[cite\]10.14469/ch/191655\[/cite\] |

The energies of the three located transition states increase with the
dipole moment; as the counter-ion moves further from the positive
charge, its position becomes less stable. Still, route 2 is not that
much higher in energy. Time for an IRC (intrinsic reaction coordinate)
to explore what actually does happen during route 2, the possible Grob
rearrangement.

[![grob1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/grob1.gif){.aligncenter
.size-full .wp-image-14952 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/grob1.gif)

The reaction animation above shows the required Grob characteristic, the
green bond breaking. But instead of the OH then de-protonating, the
hydrogen stays in place and instead the Tiffeneau-Demjanov migration
takes place. This will require removal of a different proton and indeed
in the latter stages, the chloride anion starts off in its determined
journey to do so.

[![GrobDM](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/GrobDM.svg){.aligncenter
.size-full .wp-image-14953 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/GrobDM.svg)

The variation in dipole moment as the reaction proceeds is fascinating.
At IRC -6, it reaches a minimum, but then reverses itself in hunt of a
better way of reducing the dipole moment.

What about 3? This is slightly artificial, since the real system has a
methoxy group here, which would inhibit this route. One can still learn
chemistry though. The hydrogen bond formed from chloride to the OH
encourages the anomeric effect to form a partial oxy-anion, which in
turn encourages the red bond to break rather than the green one. But in
fact no complete proton transfer happens, and the reaction reaches a
non-productive cul-de-sac. 

[![Alt1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/Alt1.gif){.aligncenter
.size-full .wp-image-14955 loading="lazy" decoding="async" width="398"
height="428"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/11/Alt1.gif)

So, to conclude, there is no Grob fragmentation! Instead, a slightly
confused Tiffeneau-Demjanov migration occurs in a rather more roundabout
manner than previously. We have explored here just TWO reaction
trajectories. A more statistical exploration of the trajectory landscape
will give us a more complete picture, but I rather fancy that would be
very well above the call of duty required to answer a stereochemical
problem!

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


In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does
<strong>
 not
</strong>
happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation has to say about what does (or might) not happen.

Rogue Scholar Beiträge

A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?