Imperial College London

Henry Rzepa

The concept of a "*hidden intermediate*" in a reaction pathway has been
promoted by Dieter Cremer\[cite\]10.1021/ar900013p\[/cite\] and much
invoked on this blog. When I used this term in a recent article of
ours\[cite\]10.1021/jo401146k\[/cite\], a referee tried to object,
saying it was not in common use in chemistry. The term clearly has an
image problem. A colleague recently sent me an article to read (thanks
Chris!) about isotope effects in the epoxidation of
ethene\[cite\]10.1021/jo981652x\[/cite\] and there I discovered a nice
example of hidden intermediates which I share with you now.

[![peracid](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid.svg){.aligncenter
.size-full .wp-image-11070 decoding="async"
width="300"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid.svg)

The reaction above is considered as a transfer of an oxygen atom to an
alkene with
[concomitant](http://dictionary.reference.com/browse/concomitant){target="_blank"
rel="noopener"} concerted proton transfer (for the analogous reaction of
an alkyne [see
here](http://www.ch.imperial.ac.uk/rzepa/blog/?p=7027 "Joining up the pieces. Peroxidation of ethyne."){target="_blank"
rel="noopener"}). The mechanism is normally illustrated with five arrows
accomplishing both operations (see below). But a simple experiment shows
this cannot be accurate\[cite\]10.1021/jo981652x\[/cite\]. When
d~4~-ethene is used (with mCPBA as the peracid) in dichloromethane
solution, an *inverse* kinetic isotope effect of 0.83 is observed (in
other words the d~4~-- species reacts faster than the ^1^H). If the
peracid is instead deuterated (as OD) the reaction slows down by a
factor of 1.05 (a *normal* isotope effect). This data provides a good
test of whether any transition state model constructed for the reaction
is a good one. So how about a
ωB97XD/6-311G(d,p)/SCRF=dichloromethane\[cite\]10.6084/m9.figshare.781238\[/cite\],\[cite\]http://dx.doi.org/10.6084/m9.figshare.781240\[/cite\]
model, using per-ethanoic acid? The isotope effect can be obtained by
calculating the activation free energy with the appropriate isotope
specified.

|         |                 |             |            |                  |            |
|---------|-----------------|-------------|------------|------------------|------------|
| Value   | Normal isotopes | d~4~-ethene | OD acid    | One ^13^C-ethene | One ^18^O  |
| ΔG~298~ | 26.6844375      | 26.5589375  | 26.7245975 | 26.6907125       | 26.7296175 |
| KIE     |  --             | 0.808       | 1.070      | 1.011            | 1.080      |

Activation barriers for isotopic substitutions

The deuterium isotope effects, on both carbon and oxygen compare very
well indeed with those measured (the ^13^C and ^18^O have never been
measured, they are predictions), which greatly assures that the model is
a good one. So the predicted transition state geometry as shown below
has had a good reality check. It reveals that two O-C bonds are forming,
and the O-O bond is breaking, but that proton transfer has hardly
started. This corresponds to the three green arrows shown at the top.
The three blue arrows are not yet in action. I have colour-coded them to
illustrate this temporal aspect. 

![peracid+alkene1](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid+alkene1.jpg){.aligncenter
.wp-image-11075 loading="lazy" decoding="async" width="228"
height="286"}

An intrinsic reaction
coordinate\[cite\]10.6084/m9.figshare.781284\[/cite\] shows that the
reaction is concerted, albeit asynchronous; the transition state (**TS,
@**IRC=0.0) really only involves the green arrows; the blue arrows kick
in only **AFTER** the ion-pair-like hidden intermediate is formed,
labelled **HI** above (and seen @IRC =+1.2). Stabilising the ion-pair
using trifluorethanoic acid\[cite\]10.6084/m9.figshare.781283\[/cite\]
(a stronger acid) renders the **HI** more prominent.

|                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| [![peracid](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid1.svg){.aligncenter .size-full .wp-image-11084 decoding="async" width="440"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid1.svg) |
| ![peracidG](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracidG1.svg){.aligncenter .size-full .wp-image-11086 decoding="async" width="440"}                                                                                  |
| --![peracidF](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracidF.svg){.aligncenter .size-full .wp-image-11090 decoding="async" width="440"}                                                                                 |
| ![peracidFG](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracidFG.svg){.aligncenter .size-full .wp-image-11089 decoding="async" width="440"}                                                                                 |

As quantum calculations apparently give us trustworthy indications of
the order in which events happen during this reaction mechanism, perhaps
it is time to start representing this information in our simple
schematics. (Some) text-books currently show the left hand diagram
below, involving five arrows but with no indication of their relative
timing. The right hand side now colours the arrows to indicate that the
green precede the blue. An extra arrow is added to indicate that one
electron pair is involved in forming a "hidden intermediate", the green
arrow aspiring to end at a lone pair, but the blue arrow then continuing
its progress to the final epoxide. The end-point of one arrow
representing the start point of another could thus be taken as implying
a *hidden intermediate*.

[![peracid1](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid11.svg){.aligncenter
.size-full .wp-image-11093
decoding="async"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/08/peracid11.svg)

As I have [noted
elsewhere](http://www.ch.imperial.ac.uk/rzepa/blog/?p=10706 "Mechanistic arrow pushing. A proposed addition to its rules."){target="_blank"
rel="noopener"}, the curly-arrow representation of reaction mechanism
has hardly evolved over the last sixty years. Some might argue that such
stability is appropriate for a very simple heuristic used to teach
introductory chemistry to students, and that this very simplicity should
not be gratuitously discarded. But perhaps, in the light of what we now
know about many mechanisms, it has become over-simple? Could judiciously
deployed colour-coding^‡^ of the arrows be a useful, albeit perhaps only
a small step, to upgrading arrow pushing into the 21st century? 

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

^‡^I appreciate that some people are [red-green/blue-yellow
colour-blind](http://en.wikipedia.org/wiki/Color_blindness){target="_blank"
rel="noopener"}, and that a full ROYGBIV spectrum of colours may carry
too much information!

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


The concept of a “
<em>
 hidden intermediate
</em>
” in a reaction pathway has been promoted by Dieter Cremer[cite]10.1021/ar900013p[/cite] and much invoked on this blog. When I used this term in a recent article of ours[cite]10.1021/jo401146k[/cite], a referee tried to object, saying it was not in common use in chemistry. The term clearly has an image problem.

Messaggi di Rogue Scholar

Experimental evidence for “hidden intermediates”? Epoxidation of ethene by peracid.