The tetrahedral intermediate is one of those iconic species on which the foundation of reaction mechanism in organic chemistry is built. It refers to a (normally undetected and hence merely inferred) species formed initially when a nucleophilic reagent attacks a carbonyl compound. Its importance to understanding the activity of enzymes cannot be overstated.

Imperial College London

Henry Rzepa

The ***tetrahedral intermediate*** is one of those iconic species on
which the foundation of reaction mechanism in organic chemistry is
built. It refers to a (normally undetected and hence merely inferred)
species formed initially when a nucleophilic reagent attacks a carbonyl
compound. Its importance to understanding the activity of enzymes cannot
be overstated. An example of this genre is shown below, in which a thiol
reacts with an acyl cyanide to form the species ringed in green.

[![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/01/acetylcyanide.svg "acetylcyanide"){.aligncenter
.wp-image-6045 decoding="async"
width="440"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/01/acetylcyanide.svg)

The lifetime of such a species is normally assumed to be too short for
it to be detectable\[cite\]10.1021/jo00389a050\[/cite\], but suitable
adjustment of the substituents enables its lifetime can be extended to
many hours. Thus the reaction between PhCH~2~SH (benzyl thiol) and
acetyl cyanide occurs slowly and the resulting intermediate is stable
enough to be detected by ^1^H NMR
spectroscopy\[cite\]10.1021/ed064p725\[/cite\]. The spectrum in CDCl~3~
is shown below:

::: {#attachment_6047 .wp-caption .aligncenter style="width: 416px"}
[![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/01/acetylcyanide.jpg "acetylcyanide"){.size-full
.wp-image-6047 loading="lazy" decoding="async"
aria-describedby="caption-attachment-6047" width="406"
height="203"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/01/acetylcyanide.jpg)

Spectrum of a tetrahedral intermediate.
:::

What is shown is actually a difference spectrum, in which the spectrum
measured immediately after mixing the two reagents is subtracted from
that obtained after about 12 hours. The negative peaks represent a
species which is being replaced by one giving rise to positive peaks. It
is the nature of these latter peaks which directly prove that the
species formed after 12 hours contains an asymmetric tetrahedral carbon
atom.

1.  The negative peaks are \~δ1.8ppm (triplet), 3.8 (doublet \[assigned
    to the CH~2~SH region\], 2.6 ppm (the Me group of the acetyl
    cyanide) and 7.3 (the Ph group).
2.  The positive peaks are 1.9 ppm (Me singlet), an AB quartet at 4.2
    ppm equal in integration to the negative peak at 3.8 ppm, and a more
    disperse Ph peak.
3.  If pressure is applied\[cite\]10.1039/P29870001477\[/cite\] to the
    solution, the tetrahedral intermediate forms more quickly, and
    actually crystallises out of solution (Le Chatelier's principle).
4.  If a hydroxylamine (RNHOH) is used instead of a thiol, the
    tetrahedral intermediate forms much more
    quickly\[cite\]10.1021/jo00389a050\[/cite\], and both N: and O:
    nucleophilic isomers can be
    detected\[cite\]10.1021/jo00389a050\[/cite\] (by ^15^N-^13^C ^2^J
    couplings in the case of the former).
5.  Particularly significant is that the new product manifests its CH~2~
    group as an AB quartet. This must mean that the two methylene
    protons are diastereotopic (have different chemical shifts and hence
    the coupling between them can be observed). This cannot be achieved
    by restricted rotation (atropisomerism) and hence can only arise by
    the CH~2~ group being close to an asymmetric (chiral) carbon atom
    bearing four different groups.

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The other interesting aspect is whether the tetrahedral intermediate is
formed in two stages, the first being S-C bond formation, followed by a
proton transfer from S to O, or whether it can form directly in a single
concerted step. On the assumption that CDCl~3~ solutions contain traces
of water, a synchronous mechanism does seem possible. The water helps
transfer the hydrogen from S to O, as shown in the intrinsic reaction
coordinate\[cite\]http://hdl.handle.net/10042/to-11696\[/cite\]
animation below (wB97XD/6-311G(d,p)/SCRF=choroform calculation). Notice
how the H firstly leaves the S and hops across to the water, and only
then does another H from the water hop over to the carbonyl group. The
computed free energy barrier for this process is 22.5 kcal/mol, which is
pretty much spot on for a slow thermal reaction.

</div>

<div>

::: {#attachment_6054 .wp-caption .aligncenter style="width: 332px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/01/acylcn.gif "acylcn"){.size-full
.wp-image-6054 loading="lazy" decoding="async"
aria-describedby="caption-attachment-6054" width="322" height="232"}

IRC animation for the formation of a tetrahedral intermediate.
:::

  
[![](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2020/12/logfile-3_tot_ener.svg){.aligncenter
.size-large .wp-image-23107 decoding="async"
width="450"}](https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2020/12/logfile-3_tot_ener.svg)

</div>

The slow motion capture of a tetrahedral intermediate using substituents
finely tuned for the purpose (a relatively non nucleophilic thiol
coupled with a relatively poor cyano leaving group) enables us to
directly prove its identity using NMR. The same technique as it happens
was also used to characterise another iconic intermediate, the
carbocation, many years after it too was inferred as a key mechanistic
participant.

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[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
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The
<em>
 <strong>
  tetrahedral intermediate
 </strong>
</em>
is one of those iconic species on which the foundation of reaction mechanism in organic chemistry is built. It refers to a (normally undetected and hence merely inferred) species formed initially when a nucleophilic reagent attacks a carbonyl compound. Its importance to understanding the activity of enzymes cannot be overstated.

Postagens de Rogue Scholar

Secrets of a university tutor: tetrahedral intermediates.