Imperial College London

Henry Rzepa

The substitution of a
[nucleofuge](https://en.wikipedia.org/wiki/Nucleofuge){target="_blank"}
(a good leaving group) by a nucleophile at a carbon centre occurs with
inversion of configuration at the carbon, the mechanism being known
by the term S~N~2 (a story I have also told in this
[post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=4002){target="_blank"}).
Such displacement at silicon famously proceeds by a quite different
mechanism, which I here quantify with some calculations.

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/Si.svg){decoding="async"
width="400"}

Trialkylsilyl is often used to protect OH groups, and as shown in the
diagram above is specifically used to enforce the enol form of a ketone
by replacing the OH with OTMS. The TMS can then be removed when
required by utilising nucleophilic addition of *e.g.* fluoride anion
from tetra-alkyl ammonium fluoride to form a 5-coordinate silicon
intermediate, followed by collapse of this intermediate with expulsion
of the oxygen to form an enolate anion. Before starting the
calculations, I searched the crystal structure database for examples of
R~3~SIF(OR), as in the search query below.

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/Si-SQ.jpg){decoding="async"
width="400"}

There were 55 instances of such species, and show below are their
geometric characteristics. In all cases, the two electronegative
substituents occupy the axial positions of a **trigonal bipyramidal**
geometry. This of course is the orientation adopted by the two
electronegative substituents in the S~N~2 mechanism for carbon, but with
silicon this carbon \"transition state\" can be replaced by a stable
(and as we see often crystalline) intermediate!

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/SiOF.jpg){decoding="async"
width="400"}

Turning to calculations (ωB97XD/6-31+G(d)/SCRF=thf), one can locate
**three** transition states for the silicon process (there is only one
for the S~N~2 reaction with carbon).

1.  TS1 represents attack of fluoride anion along the axial position of
    the forming 5-coordinate
    silicon.\[cite\]10.14469/hpc/554\[/cite\],\[cite\]10.14469/hpc/564\[/cite\]
    The oxygen in this instance occupies an equatorial position, and
    this close proximity between the incoming F(-) and the about to
    depart OR groups represents a [*retention of configuration*
    ]{style="color:#FF0000;"}at the Si. Note that the reaction is
    endo-energic.
    (*c.f.* \[cite\]10.1016/S0040-4020(01)89077-3\[/cite\]).  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts1.jpg){decoding="async"
    onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/05/TS1-876.301414.log;frame 45;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;spin 3;');"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts1a.gif){decoding="async"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS1.svg){decoding="async"
    width="400"}
2.  The next step,
    TS2\[cite\]10.14469/hpc/551\[/cite\],\[cite\]10.14469/hpc/553\[/cite\] 
    is to move the F ligand to an equatorial position and the OR group
    from equatorial to its own axial position so that it can depart in
    the manner the F adopted to arrive. This requires what is called a
    [Berry pseudorotation]{style="color:#FF0000;"}, an essentially
    isoenergic process.  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts2.jpg){decoding="async"
    onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/05/TS2-876.297846.log;frame 129;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;spin 3;');"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts2.gif){decoding="async"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS2.svg){decoding="async"
    width="400"}  
    You might note a \"hidden intermediate\" at IRC \~-7 (the \"bump\"
    in the energy profile). This is caused by re-organisation of the
    ion-pair geometry, with the tetra-alkyl ammonium cation moving its
    orientation.  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS2G.svg){decoding="async"
    width="400"}
3.  TS3\[cite\]10.14469/hpc/539\[/cite\],\[cite\]10.14469/hpc/552\[/cite\]
    now eliminates the ^--^OR group to complete the deprotection.  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts3.jpg){decoding="async"
    onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/05/TS3-876.305730.log;frame 63;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;spin 3;');"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ts3.gif){decoding="async"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS3.svg){decoding="async"
    width="400"}

The free energies are summarised below. Key points include:

1.  The overall free energy of deprotection is appropriately
    exo-energic.
2.  The highest energy barrier is actually for pseudo-rotation! This
    suggests that tuning the deprotection with alternative alkyl or aryl
    groups on the silicon may be a matter of controlling the Berry
    pseudorotation process.
3.  TS1-3 proceed with the attacking and leaving groups in close
    proximity (the angle between an axial and an equatorial group is
    \~90° of course, whereas for a di-axial relationship (the inversion
    of the S~N~2 mechanism) it is instead 180°. This close proximity of
    nucleophile and nucleofuge minimises the required reorganisation of
    the ammonium counter-ion in the ion-pairs, and possibly also the
    dipole moments induced by the reactions, the changes of which for
    the three reactions are shown below:  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS1DM.svg){decoding="async"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS2DM.svg){decoding="async"
    width="400"}  
    ![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/TS3DM.svg){decoding="async"
    width="400"}
4.  The 5-coordinate intermediate where both F and O are axial is in
    fact significantly lower in energy (a cooperative effect) than when
    only one of them is axial, which matches the orientations identified
    above in the 55 crystal structures. For a substitution to occur, the
    cooperative strengthening of the Si-O and Si-F bonds must be
    removed; hence the [*retention of
    configuration*]{style="color:#FF0000;"}.

|                  |                      |                                   |
|------------------|----------------------|-----------------------------------|
| System           | Relative free energy | DataDOI                           |
| Reactants        | 0.0                  | \[cite\]10.14469/hpc/565\[/cite\] |
| TS1              | 7.9                  | \[cite\]10.14469/hpc/554\[/cite\] |
| Int F(ax), O(eq) | 5.1                  | \[cite\]10.14469/hpc/555\[/cite\] |
| TS2              | 10.2 (9.2)\*         | \[cite\]10.14469/hpc/551\[/cite\] |
| Int F(eq), O(ax) | 5.1                  | \[cite\]10.14469/hpc/540\[/cite\] |
| TS3              | 5.2                  | \[cite\]10.14469/hpc/539\[/cite\] |
| Products         | -4.0                 | \[cite\]10.14469/hpc/563\[/cite\] |
| Int F,O(ax)      | -2.5                 | \[cite\]10.14469/hpc/550\[/cite\] |

\*A lower energy orientation of the ion-pair has subsequently been
found.\[cite\]10.14469/hpc/577\[/cite\]

This analysis shows just how different the carbon and the silicon
substitution reactions are and how it is the pseudorotation
interconverting two 5-coordinate intermediates that appears to be a key
step. But questions remain unanswered. What is the energy of
the pseudorotation interconverting an intermediate with **ax/eq**
electronegative groups to one with **di-axial** electronegative groups?
Are there transition states starting from the diaxial intermediate and
resulting in elimination, and if so what are their relative energies? I
leave answers to a follow up post. 

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


The substitution of a nucleofuge (a good leaving group) by a nucleophile at a carbon centre occurs with inversion of configuration at the carbon, the mechanism being known by the term S
<sub>
 N
</sub>
2 (a story I have also told in this post). Such displacement at silicon famously proceeds by a quite different mechanism, which I here quantify with some calculations.

Messaggi di Rogue Scholar

The mechanism of silylether deprotection using a tetra-alkyl ammonium fluoride.