Imperial College London

Henry Rzepa

My previous dissection of the mechanism for ester hydrolysis dealt with
the acyl-oxygen cleavage route ([[red
bond]{style="color: #ff0000;"}](http://www.ch.imperial.ac.uk/rzepa/blog/?p=10015){target="_blank"}).
There is a much rarer\[cite\]10.1039/jr9550001522\[/cite\] alternative:
alkyl-oxygen cleavage ([green bond]{style="color: #339966;"}) which I
now place under the microscope.

![alkyl-ester](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkyl-ester.svg){.aligncenter
.size-full .wp-image-10074 decoding="async" width="400"}

Here, guanidine is used as a general acid/base, which results in a
reasonable activation barrier for the hydrolysis (using pure water as
the catalyst led to high barriers). What I will call the classical
stepwise route is shown above, with charge-separated structures in
abundance (particularly at the allyl group, where the possibility of
forming a carbocation at this centre is central to the mechanism). My
philosophy here is to allow quantum mechanics to decide whether to
separate charge or not (in effect, only it is allowed decisions about
where electrons are). So one can start with a concerted mechanism in
which no formal charges are separated, and by subjecting them to
wB97XD/6-311G(d,p)/SCRF=water calculation, decide where and if charges
develop.

There are two distinct possibilities; hydrolysis with either retention
or inversion of configuration at the alkyl group. The results for the
transition states are shown below, with the analogous energy for
acyl-oxygen cleavage shown for comparison.

|                                                   |                                                                          |                                                                   |                                                                           |
|---------------------------------------------------|--------------------------------------------------------------------------|-------------------------------------------------------------------|---------------------------------------------------------------------------|
| Relative energies for hydrolysis of Alkyl acetate |                                                                          |                                                                   |                                                                           |
| R                                                 | Acyl-oxygen                                                              | Alkyl O,inversion                                                 | Alkyl-O,retention                                                         |
| all H                                             | [0.0](http://hdl.handle.net/10.6084/m9.figshare.660839){target="_blank"} | [15.3](http://hdl.handle.net/10042/24455){target="_blank"}        | [42.5](http://hdl.handle.net/10.6084/m9.figshare.663607){target="_blank"} |
| Me                                                | [0.0](http://hdl.handle.net/10042/24454){target="_blank"}                | [16.6](http://hdl.handle.net/10042/24456){target="_blank"}        | [35.0](http://hdl.handle.net/10042/24450){target="_blank"}                |
| Me,Me                                             | [0.0](http://hdl.handle.net/10042/24453){target="_blank"}                | [16.3](http://hdl.handle.net/10042/24463){target="_blank"}        | [18.2](http://hdl.handle.net/10.6084/m9.figshare.663618){target="_blank"} |
| Me,Me,Me                                          | [0.0](http://hdl.handle.net/10.6084/m9.figshare.663604){target="_blank"} | [16.4 (14.4)](http://hdl.handle.net/10042/24461){target="_blank"} |  ?                                                                        |

For R1=R2=R3=H and R1=Me,R2=R3=H proceeding with **retention of
configuration. T**he IRCs are as below, which reveal a "hidden
intermediate" feature (visible as a dip in the gradient norm), which
corresponds to a charge-separated zwitterionic intermediate immediately
preceding the proton transfer. In other words, the non-charge-separated
cyclic/concerted mechanism shown above is "interrupted" by charge
separation in a hidden way ***during***, and in an explicit way ***at***
the final stage, preferring finally to form the ionic ion-pair rather
than neutral acetic acid and guanidine.

|                                                                                                                                                                                                                              |                                                                                                                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![alkylg](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkylg.gif){.aligncenter .wp-image-10094 loading="lazy" decoding="async" width="218" height="242"}\[cite\]10.6084/m9.figshare.663603\[/cite\]   | ![alkylg](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkylg.svg){.aligncenter .size-full .wp-image-10093 decoding="async" width="220"}   |
| ![alkylMe](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkylMe.gif){.aligncenter .wp-image-10092 loading="lazy" decoding="async" width="203" height="234"}\[cite\]10.6084/m9.figshare.663619\[/cite\] | ![alkylMe](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkylMe.svg){.aligncenter .size-full .wp-image-10091 decoding="async" width="220"} |
| ![alkylMeG](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/alkylMeG.svg){.aligncenter .size-full .wp-image-10090 decoding="async" width="300"}                                                           |                                                                                                                                                                  |

For R1=R2=Me, R3=H, we have a change. The C-O bond lengths at the
solvolysing methyl increase as the substitution at this carbon
increases, e.g. 2.2Å (R=H) → 2.4Å (R1=Me) as the transition state
becomes more carbocation like. With increasing carbocationic character,
the acidity of the adjacent C-H group increases, until with R1=R2=Me,
R3=H it has become acidic enough to be abstracted by any close-by base
(in this instance, guanidine). Experimentally, the aqueous hydrolysis of
t-butyl acetate is known to proceed with alkyl-oxygen
cleavage\[cite\]10.1039/jr9550001522\[/cite\]. In the computational
model, the solvolysis mechanism has been intercepted by an elimination
mechanism: the two potential surfaces under these circumstances are very
close and they merge to ensure a different outcome of the reaction. You
can see this effect below;

::: {#attachment_10129 .wp-caption .aligncenter style="width: 240px"}
![alkylG-Me2](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/alkylG-Me2.gif){.wp-image-10129
loading="lazy" decoding="async"
aria-describedby="caption-attachment-10129"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/04/alkylG-Me2.log;frame 153;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 10;animation mode loop;');"
width="230" height="269"}

Click for 3D.
:::

The reaction barrier also drops as the degree of substitution at the
migrating carbon increases. At time of writing, no TS had been located
for R1=R2=R3 (? in table above) but as you can see the trend could
easily take it below the energy for acyl oxygen hydrolysis.

A much lower energy route however is apparently available for the
alkyl-oxygen solvolysis route. For R1=R2=R3=H, it proceeds much more
favourably with inversion of configuration, an intramolecular Sn2
solvolysis in fact.

|                                                                                                                                                                          |                                                                                                                                                                          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![alkylg-inva](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/alkylg-inva.gif){.aligncenter .size-full .wp-image-10127 decoding="async" width="220"} | ![alkylg-inva](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/alkylg-inva.svg){.aligncenter .size-full .wp-image-10126 decoding="async" width="210"} |
| ![alkylg-invg](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/alkylg-invg.svg){.aligncenter .size-full .wp-image-10125 decoding="async" width="300"} |                                                                                                                                                                          |

That for R1=R2=R3 shows a qualitative difference, in resembling the
mechanism for [Sn1 solvolysis of t-butyl
chloride](http://www.ch.imperial.ac.uk/rzepa/blog/?p=5228){target="_blank"}
in water. In this case the bond O-C bond labelled 2.3 is cleaving,
whilst the C-O bond labelled 3.1 has not yet started to form; an
apparently classical Sn1 solvolysis. But take a look at the two atoms
labelled \[1\] and \[2\]; this C-H bond is also set up to be abstracted
by an adjacent base (the carboxylate), and indeed an IRC shows the
formation of butene (not solvolysis) to be the final outcome. 

::: {#attachment_10134 .wp-caption .aligncenter style="width: 241px"}
![Click for
3D.](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/04/alkylG-Me3-inv.gif){.wp-image-10134
loading="lazy" decoding="async"
aria-describedby="caption-attachment-10134"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/04/alkylG-Me3-inv-667.876595.log;frame 3;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 10;animation mode loop;');"
width="231" height="206"}

Click for 3D.
:::

Unlike the mechanism involving retention of configuration, the barrier
for the inversion route does not change much as the substitution at the
carbon increases, remaining above the acyl-oxygen solvolysis for even
the t-butyl ester (R1=R2=R3=Me). 

To summarise what we might have learnt. Firstly, the mechanism of the
apparently simple hydrolysis of alkyl esters of ethanoic (acetic) acid
suddenly got much more complicated. It might seem that solvolysis of the
O-alkyl bond can proceed with either inversion or retention of
configuration at the alkyl carbon; if the latter then the barrier seems
to decrease as the stabilisation of the carbocation at this carbon
increases. But for both retention and inversion, the mechanistic pathway
can easily be subverted by a different reaction involving the formation
of an alkene.

One starts to suspect that the model I am using here to study this
reaction may be either the wrong kind, or certainly incomplete. In the
absence of any explicit water (merely a continuum model acting on its
behalf), it seems more basic molecules bound in by hydrogen bonds
(guanidine or carboxylate) can take over by acting as bases and
abstracting hydrogens from a H-C bond adjacent to the carbocationic
centre. In order to redirect the mechanism onto the solvolysis pathway,
one probably needs to have a few more explicit water molecules hanging
around (so to speak) so as to quickly intercept the forming carbocation,
before it can release its proton to the base. In other words, one needs
to set up a more statistical model, in which the probability of the
desired outcome is in part determined by the probability of having a
favourable molecule adjacent to the reacting centre. Who would have
thought such a basic prototype for organic chemistry could be so tricky
to pin down in a computational model! 

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


My previous dissection of the mechanism for ester hydrolysis dealt with the acyl-oxygen cleavage route (red bond). There is a much rarer[cite]10.1039/jr9550001522[/cite] alternative: alkyl-oxygen cleavage (green bond) which I now place under the microscope.

Rogue Scholar Beiträge

The mechanism of ester hydrolysis via alkyl oxygen cleavage under a quantum microscope