Imperial College London

Henry Rzepa

White City is a small area in west london created as an exhibition site
in 1908, morphing over the years into an Olympic games venue, a
greyhound track, the home nearby of the BBC (British Broadcasting
Corporation) and most recently the new western campus for Imperial
College London.^♣^ The first Imperial department to move into the MSRH
(Molecular Sciences Research Hub) building is chemistry. As a personal
celebration of this occasion, I here dedicate three transition states
located during my first week of occupancy there, naming them the White
City trio following
earlier [inspiration](http://www.perivalepark.london/?p=18719) by a
[string trio](https://www.trio-oreade.ch/) and their own instruments.

The chemistry revisits the mechanism of amide formation from an acid and
an amine, which I [first
described](https://www.ch.imperial.ac.uk/rzepa/blog/?p=13047) on this
blog about four years ago. I had constructed a model of one amine and
one carboxylic acid, to which I added a further acid in recognition that
proton transfers are a key aspect of the mechanism. When the model is
quantified using quantum calculations
(ωB97XD/6-311G(d,p)/SCRF=p-toluene) it resulted in a free energy
barrier ΔG~298~^‡^ of about 22 kcal/mol. Re-reading what I wrote, I see
I did rather gloss over this value, which implies a decently rapid
reaction! In fact, the reaction occurs relatively slowly at the
temperature of refluxing toluene. Perhaps some alarm bells should have
been tinkling at this stage (although the sluggish reaction might for
example instead be due to poor solubility) and so here I have a rethink
of the model used to see if that modest barrier really is correct.

The new premise is to test if the required proton transfers can instead
be mediated using a second molecule of amine instead of acid; thus two
molecules of carboxylic acid are now accompanied by two of amine, one of
which will be used to transfer protons. The second acid is retained to
facilitate comparison. As before, the mechanism is characterised by
three transition states and two tetrahedral intermediates. The new
mechanism is summarised below, with [**TS1-3**]{style="color: #ff0000;"}
being the White City
Trio.![](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/thewhitecity-page001.svg){.aligncenter
.size-full .wp-image-19868 decoding="async" width="450"}

The free energies are summarised in the table below. TS3, the rate
limiting step, is slightly lower in energy if the amine is used for the
proton transfer than *via* carboxylic acid. This is the wrong direction;
we really want the barrier to increase to explain the relative
difficulty of the reaction as observed in refluxing toluene! Fear not
however, the new barrier is indeed a much more sluggish 28.6 kcal/mol
(30.5 using a larger basis set).

<table data-border="1">
<colgroup>
<col style="width: 33%" />
<col style="width: 33%" />
<col style="width: 33%" />
</colgroup>
<tbody>
<tr class="header">
<th>Species
(FAIR Data DOI <a
href="https://data.hpc.imperial.ac.uk/resolve?doi=4598">10.14469/hpc/4598</a>)</th>
<th>ΔG298 (ΔG298‡)
kcal/mol</th>
<th>Structure</th>
</tr>
&#10;<tr class="odd">
<td>Ionic reactants</td>
<td><a
href="https://search.datacite.org/works?query=subjectScheme:Gibbs_energy+subject:-649.737562">-649.737562</a>♥
(0.0)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/R.jpg"
class="size-large wp-image-19835" decoding="async" width="200" /></td>
</tr>
<tr class="even">
<td>TS1 (N-C bond formation via acid PT)</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.702436*">-649.702436</a>
(22.0)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS1.jpg"
class="size-full wp-image-19841" decoding="async" width="200" /></td>
</tr>
<tr class="odd">
<td>TS1 (N-C bond formation via amine PT), the “White City”</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.702307*">-649.702307</a>
(22.1)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS1a-e1533534652441.jpg"
class="aligncenter size-full wp-image-19866" decoding="async"
width="200" /></td>
</tr>
<tr class="even">
<td>TI1 from TS1</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.709938*">-649.709938</a>
(17.3)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TI1-e1533477789356.jpg"
class="aligncenter size-full wp-image-19857" decoding="async"
width="200" /></td>
</tr>
<tr class="odd">
<td>TS2 (PT from N to O via acid PT)</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.713027*">-649.713027</a>
(15.4)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS2-e1533459631896.jpg"
class="aligncenter size-full wp-image-19843" decoding="async"
width="200" /></td>
</tr>
<tr class="even">
<td>TS2 (PT from N to O via amine PT), the “White City”</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.706042*">-649.706042</a></td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS2-e1533459631896.jpg"
class="aligncenter size-full wp-image-19843" decoding="async"
width="200" /></td>
</tr>
<tr class="odd">
<td>TI2 from TS2</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.711481*">-649.711481</a>
(16.4)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TI2-e1533471720466.jpg"
class="aligncenter size-full wp-image-19854" decoding="async"
width="200" /></td>
</tr>
<tr class="even">
<td>TS3 (O-C bond cleavage via amine PT), the “White City”</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.691918*">-649.691918</a>
(28.6) [30.5]‡</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS3-e1533459816908.jpg"
class="aligncenter size-full wp-image-19844" decoding="async"
width="200" /></td>
</tr>
<tr class="odd">
<td>TS3 (O-C bond cleavage via acid PT)</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.689910*">-649.689910</a>
(29.9)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/TS3a-e1533459990683.jpg"
class="aligncenter size-full wp-image-19845" decoding="async"
width="200" /></td>
</tr>
<tr class="even">
<td>Non-ionic product from TS3</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.732417*">-649.732417</a>
(+3.2)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/Pa-e1533471892985.jpg"
class="aligncenter size-full wp-image-19855" decoding="async"
width="200" /></td>
</tr>
<tr class="odd">
<td>Ionic product after PT</td>
<td><a
href="https://commons.datacite.org/?query=subjects.subjectScheme:Gibbs_Energy+AND+subjects.subject:\-649.741246*">-649.741246</a>
(-2.3)</td>
<td><img
src="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/P-e1533460191513.jpg"
class="size-full wp-image-19847" decoding="async" width="200" /></td>
</tr>
</tbody>
</table>

How did this happen? It's the
[reactants](https://search.datacite.org/works?query=subjectScheme:Gibbs_energy+subject:-649.737562)!
The original reactant model was based on the known structure of acetic
acid dimer, with an amine weakly hydrogen bonded. Adding an extra amine
now allows an entirely new motif to form, in which the amine disrupts
the acetic dimer to form a cyclic system with a pair of very strong
(-)O-H-N(+)-H-O(-) hydrogen bond units.† The original model did not have
sufficient components to fully allow this to happen.

![](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/reactants-1024x719.jpg){.size-large
.wp-image-19933 loading="lazy" decoding="async" width="450" height="316"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/reactants-1024x719.jpg 1024w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/reactants-300x211.jpg 300w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/reactants-768x539.jpg 768w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2018/08/reactants.jpg 1958w"
sizes="(max-width: 450px) 100vw, 450px"}So the White City Trio achieve a
performance which helps explain why a reaction is sluggish rather than
facile (normally one strives to show the opposite). Perhaps however it
should be the White City quartet, in recognition that the reactant also
had a role to play?

------------------------------------------------------------------------

^♣^A photograph of the building under construction can be seen
[here](https://www.ch.imperial.ac.uk/rzepa/blog/?p=14515).
^‡^Def2-TZVPPD basis set. ^†^There does not appear to be a recorded
structure for methylammonium acetate. We hope to obtain one to check
what the extended structure actually is. ^♥^I will elaborate an
interesting new use of this value in a [separate
post](https://www.ch.imperial.ac.uk/rzepa/blog/?p=19892).

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

White City is a small area in west london created as an exhibition site in 1908, morphing over the years into an Olympic games venue, a greyhound track, the home nearby of the BBC (British Broadcasting Corporation) and most recently the new western campus for Imperial College London.

 ♣

The first Imperial department to move into the MSRH (Molecular Sciences Research Hub) building is chemistry.

Rogue Scholar Beiträge

The “White City Trio” – The formation of an amide from an acid and an amine in non-polar solution (updated).