Imperial College London

Henry Rzepa

The diazo-coupling reaction dates back to the 1850s (and a close
association with Imperial College *via* the first professor of chemistry
there, [August von
Hofmann](http://en.wikipedia.org/wiki/August_Wilhelm_von_Hofmann){target="_blank"})
and its mechanism was much studied in the heyday of physical organic
chemistry.\[cite\]10.1021/ja00830a009\[/cite\] Nick Greeves, purveyor of
the excellent [ChemTube3D](http://www.chemtube3d.com){target="_blank"}
site, contacted me about the transition state (I have [commented
previously](http://www.ch.imperial.ac.uk/rzepa/blog/?p=2423 "The oldest reaction mechanism: updated!"){target="_blank"}
on this aspect of aromatic electrophilic substitution). ChemTube3D
recruits undergraduates to add new entries; Blue Jenkins is one such
adding a section on dyes.

[![diazonium](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazonium.svg){.aligncenter
.size-full .wp-image-12057 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazonium.svg)

The mechanism can be rate limiting either in the initial electrophilic
attack (black arrows) or in the subsequent proton removal (red arrows
using an intermolecular base such as chloride
anion).\[cite\]10.1039/P29750001209\[/cite\].^‡^ The product is normally
assumed to be the *trans*-diazo compound rather than *cis*. This
distribution is certainly true in the crystal structure database (below,
although some examples of *cis* are known, including azobenzene itself).
Would this distribution be reflected in the transition states? Initial
attempts by the ChemTube3D team had resulted only in a *cis*-transition
state being located, and they asked me to check this out.

[![diazo](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazo.jpg){.aligncenter
.wp-image-12060 decoding="async" width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazo.jpg 831w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazo-300x125.jpg 300w"
sizes="(max-width: 831px) 100vw, 831px"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/diazo.jpg)

ωB97XD/6-311G(d,p)/SCRF=water calculations using phenyl diazonium
chloride (I do like my counter-ions) coupling to benzene resulted in
location of both *cis*\[cite\]10.6084/m9.figshare.956138\[/cite\] and
*trans*\[cite\]10.6084/m9.figshare.956139\[/cite\] transition states,
the former being the **lower** by 1.0 kcal/mol in free energy (this
might well be due to the dispersion stabilisation from π-π stacking).^†^
The IRC for the *cis* is shown
below.\[cite\]10.6084/m9.figshare.956209\[/cite\]

[![cis-diazo](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazo.gif){.aligncenter
.size-full .wp-image-12085 loading="lazy" decoding="async" width="465"
height="377"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazo.gif)[![cis-diazoE](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazoE.svg){.aligncenter
.size-full .wp-image-12092 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazoE.svg)[![cis-diazoG](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazoG.svg){.aligncenter
.size-full .wp-image-12087 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/cis-diazoG.svg)

You can see that the entire process is concerted. The Wheland
intermediate normally invoked as part of the mechanism of aromatic
electrophilic substitution is not a proper intermediate but a hidden one
for the reaction with X=Y=H. The reaction coordinate has a flat top, and
that passage along this part represents the hidden Wheland. The reaction
barrier is high however, and it is certainly observed that only
activated arenes (phenols, anilines, X,Y=OH, NH~2~) actually couple with
diazonium cations. For these, the hidden intermediate is stabilized by
the substituent, and no doubt emerges as a real intermediate.

For my thesis work, I studied\[cite\]10.1039/P29750001209\[/cite\]
diazo-coupling of
[indoles](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9706 "Kinetic vs Thermodynamic control. Subversive thoughts for electrophilic substitution of Indole."){target="_blank"}.
I might have a go at returning to that work, to see if calculations can
replicate my finding, that for unhindered indoles proton removal from
the Wheland intermediate is fast, but add a few t-butyl hindering groups
and it becomes slow.

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

**PS**. Here is the IRC for the formation of
*trans*-diazobenzene.\[cite\]10.6084/m9.figshare.956213\[/cite\]

[![trans](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/trans.gif){.aligncenter
.size-medium .wp-image-12106 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2014/03/trans.gif)

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

^‡^Such diazo compounds make up a significant proportion of the 50 or so
real molecules I have personally added to the collection of 84 million
or so thus far identified.

^†^Working with ions has one statistical problem that covalent systems
do not have; where to geometrically place the counter-ion. One should
really stochastically explore reasonable locations before concluding the
likely location of the globally lowest energy pose.

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The diazo-coupling reaction dates back to the 1850s (and a close association with Imperial College
<em>
 via
</em>
the first professor of chemistry there, August von Hofmann) and its mechanism was much studied in the heyday of physical organic chemistry.[cite]10.1021/ja00830a009[/cite] Nick Greeves, purveyor of the excellent ChemTube3D site, contacted me about the transition state (I have commented previously on this aspect of aromatic

Messaggi di Rogue Scholar

The mechanism of diazo coupling: more hidden mechanistic intermediates.