tpap[cite]10.1055%2Fs-1994-25538[/cite], as it is affectionately known, is a ruthenium-based oxidant of primary alcohols to aldehydes discovered by Griffith and Ley.

Imperial College London

Henry Rzepa

***tpap***\[cite\]10.1055%2Fs-1994-25538\[/cite\], as it is
[affectionately
known](http://en.wikipedia.org/wiki/Tetrapropylammonium_perruthenate){target="_blank"},
is a ruthenium-based oxidant of primary alcohols to aldehydes discovered
by Griffith and Ley. Whereas ruthenium tetroxide (RuO~4~) is a voracious
oxidant\[cite\]10.1139/v76-304\[/cite\], its radical anion countered by
a tetra-propylammonium cation is considered a more moderate
animal\[cite\]10.1021/jo00038a009\[/cite\]. In this post, I want to try
to use quantum mechanically derived energies as a pathfinder for
exploring what might be going on (or a reality-check if you like). 

 

![tpap](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap.svg){.aligncenter
.size-full .wp-image-8777 decoding="async" width="420"}

A basic (*i.e.* simple) mechanism for oxidation of an alcohol by RuO~4~
is shown above. Here I reality-check this mechanistic pathway with the
help of ωB97XD/Def2-SVPP/SCRF=dichloromethane calculations. I should
point out that since the mechanism is going to involve ion-pairs, it is
particularly important to adopt a solvent=corrected model from the
outset\[cite\]10.1021/jo100920e\[/cite\].
[TS1](http://doi.org/10.6084/m9.figshare.105494){target="_blank"} is the
transition state for addition of the alcohol to the metal, a process
which involves a synchronous proton transfer for the singlet electronic
state.

<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_8779" class="wp-caption aligncenter"
style="width: 210px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-ts1.jpg"
class="wp-image-8779" decoding="async"
aria-describedby="caption-attachment-8779"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2012/12/RuO5+ethanol-PT-550.169836.log;frame 11;connect (atomno=13) (atomno=5) PARTIAL;connect (atomno=13) (atomno=3) PARTIAL;connect (atomno=3) (atomno=12) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 20;animation mode loop;&#39;);"
width="200" alt="TS1. Click for 3D" />
<p>TS1 as a singlet. Click for 3D</p>
</div></td>
<td><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-TS1.gif"
class="aligncenter size-full wp-image-8785" decoding="async" width="200"
alt="tpap-TS1" /></td>
</tr>
</tbody>
</table>

Next comes
[TS2](http://doi.org/10.6084/m9.figshare.105482){target="_blank"}, which
involves a hydride abstraction with concomitant reduction of the
oxidation number of Ru(VIII) to Ru(VI). It is higher in free energy than
TS1 by 1.1 kcal/mol. The barrier corresponds to ΔG~298~^‡^ 37.1
kcal/mol. The process completes by low energy elimination of water
([TS3](http://doi.org/10.6084/m9.figshare.105597){target="_blank"}) from
the Ru(VI) species to give RuO~3~, which either undertakes further
oxidisation to give RuO~2~, or might instead be re-oxidized back to
RuO~4~ by oxygen (or an amine N-oxide) to complete a catalytic cycle.

<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_8779" class="wp-caption aligncenter"
style="width: 210px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-ts2.jpg"
class="wp-image-8779" decoding="async"
aria-describedby="caption-attachment-8779"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2012/12/RuO4+ethanol-singlet-ts-550.168113.log;frame 27;connect (atomno=3) (atomno=12) PARTIAL;connect (atomno=7) (atomno=2) PARTIAL;connect (atomno=7) (atomno=1) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 20;animation mode loop;&#39;);"
width="200" alt="TS1. Click for 3D" />
<p>TS2 as a singlet. Click for 3D</p>
</div></td>
<td>–<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-TS2.gif"
class="aligncenter size-full wp-image-8794" decoding="async" width="210"
alt="tpap-TS2" /></td>
</tr>
<tr class="even">
<td><div id="attachment_8811" class="wp-caption aligncenter"
style="width: 220px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/TS2-triplet.jpg"
class="size-full wp-image-8811" decoding="async"
aria-describedby="caption-attachment-8811"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2012/12/RuO4+ethanol-triplet-ts-550.182192.log;frame 11;connect (atomno=3) (atomno=12) PARTIAL;connect (atomno=7) (atomno=2) PARTIAL;connect (atomno=7) (atomno=1) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 20;animation mode loop;&#39;);"
width="210" alt="TS2 as a triplet. Click for 3D" />
<p>TS2 as a triplet. Click for 3D</p>
</div></td>
<td><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/RuO4-ts2-triplet.gif"
class="aligncenter size-full wp-image-8813" decoding="async" width="210"
alt="RuO4-ts2-triplet" /></td>
</tr>
</tbody>
</table>

Right away, we have a problem; ΔG~298~^‡ ^37.1 kcal/mol is too high to
be a realistic pathway, and yet RuO~4~ is a known
oxidant\[cite\]10.1139/v76-304\[/cite\]. One way out is to see if the
triplet state energy of this system might be lower. Whilst the
triplet-state reactant is higher in energy (by 27.5 kcal/mol) ,
[TS2](http://doi.org/10.6084/m9.figshare.105596){target="_blank"}  is
lower and corresponds to a reduced barrier of ΔG~298~^‡^ 28.2 kcal/mol.
Better, but a (small?) question mark still remains, since one would
really expect the barrier to be \~20 kcal/mol or less for a "voracious
oxidant". Perhaps the incursion of triplets makes it indiscriminate? The
spin density at the transition state is shown below, it extends across
both oxygen, carbon and Ru.

![ts2-triplet-spin](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/ts2-triplet-spin.jpg){.aligncenter
.wp-image-8817 loading="lazy" decoding="async" width="207" height="130"}

The ***tpap*** modification to this process is to use Ru(VII) in the
form of a radical anion partnered with a quaternary ammonium cation. The
basic reagent is therefore an
[ion-pair](http://doi.org/10.6084/m9.figshare.105613){target="_blank"},
hence the solvation approach mentioned earlier is needed to describe the
energetics of such a species. The R alkyl groups here are modelled as
methyl rather than propyl.

![tpap1](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap1.svg){.aligncenter
.size-full .wp-image-8799 decoding="async"}

[TS2](http://doi.org/10.6084/m9.figshare.105496){target="_blank"} for
this radical-ion-pair is shown below, and it has ΔG~298~^‡^ 30.8
kcal/mol, 2.6 kcal/mol higher than for the un-moderated reagent. In this
case, the higher-spin [quartet
states](http://doi.org/10.6084/m9.figshare.105600){target="_blank"} are
higher  in energy (by at least \~7.9 kcal/mol) and so do not
participate. 

|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![tpap-ts2](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-ts21.jpg){.aligncenter .size-full .wp-image-8821 decoding="async" onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/12/tpap-doublet-ts-764.279774.log;frame 31;connect (atomno=3) (atomno=12) PARTIAL;connect (atomno=7) (atomno=2) PARTIAL;connect (atomno=7) (atomno=1) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 20;animation mode loop;');" width="410"} |

The spin density for tpap-TS2 also reveals it to be concentrated on Ru
and one oxygen. Little is transferred to the ethanol, and we might infer
then that this TS corresponds to transfer of two-electrons from the
ethanol to the Ru-oxidant. This corresponds to Ru(VII) being reduced to
Ru(V), *i.e.* a 2-electron oxidation/reduction. Unfortunately, an
attempt to chart the reaction across a whole reaction coordinate (IRC)
failed with SCF-convergence problems, which might suggest a change in
the spin-configuration during this process. A more sophisticated
multi-configurational approach might be needed to properly establish the
electron dynamics of what is turning out to be a more complex reaction
than first seemed.

![tpap-ts2-spin-density](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/tpap-ts2-spin-density.jpg){.aligncenter
.wp-image-8823 decoding="async" width="410"}

It is time to sum up what might have been learnt.

1.  A reality check on the energetics of a viable-looking mechanistic
    route can establish whether such a mechanism does have a low enough
    free-energy to be viable at (in this case) room temperatures.
2.  In fact, observing that our initial mechanism had too high an energy
    led us to discover a triplet-state path that was significantly lower
    in energy. However, even this is still a bit too high.
3.  The ***tpap-variation*** of the oxidant, which enforces a
    doublet-state upon the mechanism,has a barrier which appears to be
    similar to the triplet-state RuO~4~ mechanism. This too may be too
    high in energy. At least we can probably rule out a quartet-state
    mechanism.
4.  And so it seems appropriate to end here by noting that
    experimentally\[cite\]10.1021/jo00038a009\[/cite\] the kinetics of
    tpap oxidations appear to be autocatalytic. The rate speeds up once
    some RuO~3~ (or RuO~2~) has been formed, and this suggests that
    perhaps a binuclear system containing two Ru atoms is a faster
    oxidant than the mononuclear variety. This reminds of the mechanism
    for Sharpless perepoxidation, where two metal centres were needed to
    control the stereochemistry.

So after all of this, we have not really found an explanation of why
tpap is a more selective and moderate oxidant than the rapacious RuO~4~.
But perhaps this is because more complex models with more than one
Ru-atom need to be constructed. This would in turn allow the oxidative
hydride abstraction from the alcohol to occur in a larger (7) ring
transition state, which is always the preferred geometry for such
transfers. If I find such, I will report back here.

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


<em>
 <strong>
  tpap
 </strong>
</em>
[cite]10.1055%2Fs-1994-25538[/cite], as it is affectionately known, is a ruthenium-based oxidant of primary alcohols to aldehydes discovered by Griffith and Ley.

Messaggi di Rogue Scholar

How to tame an oxidant: the mysteries of “tpap” (tetra-n-propylammonium perruthenate).