Imperial College London

Henry Rzepa

The mechanism of ester hydrolysis is a staple of examination questions
in organic chemistry. To get a good grade, one might have to reproduce
something like the below. Here, I subject that answer to a reality
check.

![actyl](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/actyl.svg){.aligncenter
.size-full .wp-image-10018 decoding="async" width="420"}

In this scheme, HA is a general acid, R=Me, and the net result is to
break what is called the acyl-oxygen bond (red). The mechanism is
actually incomplete, since the label PT designates a proton-transfer
(the mechanism for which is left somewhat undefined). Additionally, a
lot of charges come and go and five steps or so are involved. So a
student might be tempted to "fast-track" the whole process. Below I show
two such fast-tracks (I prefer to say simplifications):

![acetyl-ester1](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetyl-ester1.svg){.aligncenter
.size-full .wp-image-10019 decoding="async" width="300"}

In the [**blue mechanism**]{style="color: #0000ff;"}, the role of HA is
actually played by one water molecule, and a second water is assisting
the PT step (a far more thorough analysis of the mechanism can be found
in this reference\[cite\]10.1139/V09-011\[/cite\]). The reaction is
bimolecular in ester and the HA (=water in this case). The third water
would make it a termolecular reaction overall, but if the reaction takes
place in water itself than \[H~2~O\] would be constant. It would
correspond to what the text books call A~AC~2 since we consider one
molecule as an acid HA. But, one could look at it differently and
consider the second water as a nucleophile generated by concurrent
deprotonation (by the first water). This would make it a B~AC~2 type. It
turns out that if one makes the mechanism cyclic, the A~AC~2 and B~AC~2
annihilate each other in effect to create a single (peri)cyclic
mechanism (which has no well known name, but might be referred to as the
co-operative pathway). Such a mechanism can be extended using a third
water molecule ([magenta diagram]{style="color: #ff00ff;"}); I will come
to the reason for including that presently.

Why would one want to even consider such mechanisms? Because, if you
look carefully, you will see no charges! Charge separation (= large
dipole moment) takes energy. It is normally thought that this energy is
more than compensated for by additional solvation (a process which is
implicit rather than explicitly shown in text-book diagrams). But if you
do not generate charge separation, you might not need that solvation
energy. I will turn to quantum mechanics to try to decide what might be
viable (I hesitate to use the term "going on"). 

A ωB97XD/6-311G(d,p)/SCRF=water model (in which solvation is
approximately included as a continuum model) calculation yields the
following for the blue mechanism.

|                                                                                                                                                                                                                                    |                                                                                                                                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![acyl-ester](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acyl-ester.gif){.aligncenter .wp-image-10021 loading="lazy" decoding="async" width="232" height="217"}\[cite\]10.6084/m9.figshare.661351\[/cite\] | ![acyl-ester](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acyl-ester.svg){.aligncenter .size-full .wp-image-10022 decoding="async" width="210"} |

1.  Points to note are that it is concerted, in other words the quantum
    mechanics tells us that all the bonds CAN make and break in a single
    concerted process within a single kinetic step.
2.  The mechanism has an uncanny resemblance to the [nucleophilic
    aromatic
    substitution](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9917 "Concerted vs stepwise (Meisenheimer) mechanisms for aromatic nucleophilic substitution."){target="_blank"}
    I reported a couple of posts ago! It resembles an Sn2 displacement
    at an sp^2^ centre. Such juxtaposition of these two mechanisms is
    also not found in text-books. Recollect that with such aromatic
    substitution, it was possible to get both cncerted and stepwise
    mechanisms, depending on the substituents. Perhaps the same might be
    possible here?
3.  However, the energy barrier for the process with the substituents
    shown above (\~45 kcal/mol) is rather too high (the experimental
    value is estimated as \>22
    kcal/mol\[cite\]10.1139/V09-011\[/cite\]). There may be at least
    three reasons for this;
    - **(a)** a better solvation model would be needed to lower the
      energy,
    - **(b)** the angles subtended at the transferring protons are
      strained (they optimally should be linear) and
    - **(c)** water is a very poor general acid (or base)!

But as an answer in an examination, would the blue mechanism actually be
wrong? You will have to ask the instructor setting the question how they
might respond to that, although these
authors\[cite\]10.1139/V09-011\[/cite\] certainly conclude that such a
concerted mechanism is the more "correct", at least for hydrolysis in
water without added acid or base.

Point ** (b)** above can be addressed by adding another water molecule,
as per the **[magenta mechanism ]{style="color: #ff00ff;"}**[[so as to
enlarge the ring and reduce the angular
strain.]{style="color: #000000;"}]{style="color: #ff00ff;"} But before I
present the results, I need to "normalise" the system by ALSO adding one
(solvating) water molecule to the blue route, as below, so that we can
directly compare the energies of the blue and magenta pathways.

::: {#attachment_10025 .wp-caption .aligncenter style="width: 197px"}
![Click for
3D.](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetyl-2H2O-H2O.jpg){.wp-image-10025
loading="lazy" decoding="async"
aria-describedby="caption-attachment-10025"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/03/acetyl-2H2O-H2O-497.517153.log;frame 11;vectors on;vectors 4;vectors scale 5.0; color vectors magenta; vibration 10;animation mode loop;');"
width="187" height="207"}

Click for 3D.
:::

The result is a larger ring where the angular strain is clearly reduced.
There is an entropic penalty for introducing that third water molecule,
but despite this the free energy comes out 5.5 kcal/mol lower, and the
activation barrier is also lower (\~37 kcal/mol, still rather higher
than experiment). It has been reported that incorporation of a 4th water
molecule further improves matters\[cite\]10.1139/V09-011\[/cite\].

|                                                                                                                                                                                                                                       |                                                                                                                                                                          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![acetyl3H2Oa](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetyl3H2Oa.gif){.aligncenter .wp-image-10051 loading="lazy" decoding="async" width="226" height="202"}\[cite\]10.6084/m9.figshare.661789\[/cite\]  | ![acetyl3H2Oa](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetyl3H2Oa.svg){.aligncenter .size-full .wp-image-10050 decoding="async" width="210"} |

We can also address both points **(b)** and **(c)** above by replacing
HA=H~2~O by HA=guanidiniumH^+^ (green), a better general acid. This
polar modification introduces the ability for the system to better
sustain charge separations, and indeed the initial product is now an ion
pair tetrahedral intermediate (methoxide anion and guanidinium cation)
carrying a dipole moment of 14.5D, an increase over the value for the
transition state with three waters, 9.7D. The barrier (\~21 kcal/mol)
has gone in the opposite direction, decreasing significantly compared to
the water catalysed reaction. The** tetrahedral intermediate** sits in
an energy well of \~4 kcal/mol.

![acetyl-ester2](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetyl-ester2.svg){.aligncenter
.size-full .wp-image-10029 decoding="async"}

|                                                                                                                                                                                                |                                                                                                                                                                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ![acet-g](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acet-g.gif){.aligncenter .wp-image-10042 decoding="async" width="220"}\[cite\]10.6084/m9.figshare.661791\[/cite\] | ![acet-g](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acet-g.svg){.aligncenter .size-full .wp-image-10043 decoding="async" width="210"} |

A second transition state exiting the tetrahedral intermediate has a
free energy barrier\[cite\]10.6084/m9.figshare.661799\[/cite\] about 2.5
kcal/ol lower than the one entering it.

::: {#attachment_10054 .wp-caption .aligncenter style="width: 270px"}
![Click for
3D.](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/03/acetylg-part2.gif){.wp-image-10054
loading="lazy" decoding="async"
aria-describedby="caption-attachment-10054"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/03/acetylg-550.038857.log;frame 31;vectors on;vectors 4;vectors scale 5.0; color vectors blue; vibration 10;animation mode loop;');"
width="260" height="197"}

Click for 3D.
:::

What might we have learnt? That ester hydrolysis using pure water could
proceed through a cyclic and concerted transition state, involving three
(or perhaps more) water molecules passing a proton baton along the
chain, and in the process avoiding any large build up of charge
separation. Replace two of these waters with say guanidine as a general
acid/conjugate base capable of conjugatively stabilising
charge-separated species and the mechanism changes to a stepwise
reaction involving a dipolar tetrahedral intermediate sitting in a
relatively shallow energy well.

Not possibly a picture that we might expect a student sitting an
introductory examination in organic chemistry to reflect in its
entirety, but also one that perhaps the text-books might start to hint
at? Or: at some stage, armed  merely with a "smart
watch-cum-supercomputer", a student taking such an exam might respond by
performing the calculations described here as their submitted answer?
Well, not for a year or two perhaps. But it has to be said that
everything you see in this post was performed over less than two days of
elapsed time, so these "reality checks" are not that time-consuming.
Whether you choose to believe them or not of course is another matter.

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


The mechanism of ester hydrolysis is a staple of examination questions in organic chemistry. To get a good grade, one might have to reproduce something like the below. Here, I subject that answer to a reality check.

Messaggi di Rogue Scholar

A sideways look at the mechanism of ester hydrolysis.