Imperial College London

Henry Rzepa

Kinetic isotope effects have become something of a lost art when it
comes to exploring reaction mechanisms. But in their heyday they were
absolutely critical for establishing the mechanism of the benzidine
rearrangement\[cite\]10.1021/ja00373a028\[/cite\]. This classic
mechanism proceeds *via* *bis*protonation of diphenyl hydrazine, but
what happens next was the crux. Does this species rearrange directly to
the C-C coupled intermediate (a concerted \[5,5\] sigmatropic reaction)
or does it instead form a π-complex, as famously first suggested by
Michael Dewar\[cite\]10.1016/S0040-4039(01)82765-9\[/cite\] \[via
TS(NN\] and only then in a second step \[via TS(CC)\] form the C-C bond?
Here I explore the isotope effects measured and calculated for this
exact system.

![benzidine-KIE](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/01/benzidine-KIE.svg){.aligncenter
.size-full .wp-image-9107 decoding="async" width="420"}

It boils down to the following. It was supposed that if the mechanism
was a concerted \[5,5\] sigmatropic shift, then both the N-N and the C-C
bonds would be breaking/forming at the transition state and both N and C
isotope effects would be expected. However, if a π-complex were formed,
then either TS(NN) OR TS(CC) would be the rate determining step, and so
either a NN OR a CC isotope effect should manifest, but not BOTH. The
experiment carried out by Henry Shine and colleagues was thus expected
to be the definitive one.\[cite\]10.1021/ja00065a018\[/cite\] The
results (in aqueous ethanol, at 273K) revealed the following:
k(^2^H/^1^H) = 0.962, k(^14^C/^12^C)^‡^ = 1.013, k(^13^C/^13^C) = 1.013,
k(^15^N/^14^N) = 1.041. This might have appeared to prove conclusively
that the reaction was concerted, involving both the C-C and N-N bonds;
in other words a \[5,5\] sigmatropic rearrangement.

The quantum mechanical (closed shell) surface reveals only two separate
transition states, TS(NN) and TS(CC), and so at first sight seems to
contradict the experimental isotope inference. But the experimental
values are very unlikely to be wrong. So how can one reconcile these two
methods? Well, the answer is not to give up, but to calculate the
isotope effects for BOTH transition states, and see if either of them
matches the experimental result. Here are these calculations:

|      |              |                |                |                |
|------|--------------|----------------|----------------|----------------|
| TS   | k(^2^H/^1^H) | k(^14^C/^12^C) | k(^13^C/^13^C) | k(^15^N/^14^N) |
| CC   |  0.946       |  1.050         |  1.050         |  1.032         |
| NN   |  1.002       |  1.008         |  1.007         |  1.075         |
| Expt |  0.962       |  1.013         |  1.013         |  1.041         |

The match between experiment and theory for TS(CC) is reasonable (given
the approximations in both the theory and the difficulty of the
experiments and ensuring isotopic purities) but not so for TS(NN). But
TS(CC) is a "stepwise-concerted" reaction as a closed shell singlet; as
shown in the [ IRC computed from
TS(CC](http://www.ch.imperial.ac.uk/rzepa/blog/?p=8961){target="_blank"}). 

Yamabe and co\[cite\]10.1039/b909313c\[/cite\] have come to similar
conclusions (their model used a dication rather than an ion-pair). In
the latest twist, Ghigo *et
al*\[cite\]10.1016/j.tet.2012.01.014\[/cite\] used the same model as
here (HCl to provide protonation as an ion-pair) but identified
biradical (radical-cation) character at the transition state. The latter
group also calculated kinetic isotope
effects\[cite\]10.1002/ejoc.201001636\[/cite\] for the open shell
biradical TS, finding an even better match with experiment than above.

So this see-saw mechanism has oscillated between a stepwise π-complex,
then a direct \[5,5\] rearrangement and in more recent times using
computational modelling, a concerted \[5,5\] sigmatropic proceeding
*via* an initially formed π-complex, and (finally) *via* a multi-step
mechanism proceeding through a biradical π-complex and involving radical
coupling, which nevertheless appears to behave in some aspects as a
concerted \[5,5\] rearrangement. It is fascinating that a simple
diprotonation of a hydrazine could so readily induce biradical
character, and that such an apparently simple reaction could have so
many twists and turns!

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

^‡^ For one ^14^C-^12^C pair.

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Kinetic isotope effects have become something of a lost art when it comes to exploring reaction mechanisms. But in their heyday they were absolutely critical for establishing the mechanism of the benzidine rearrangement[cite]10.1021/ja00373a028[/cite]. This classic mechanism proceeds
<em>
 via
</em>
<em>
 bis
</em>
protonation of diphenyl hydrazine, but what happens next was the crux.

Postagens de Rogue Scholar

The Benzidine rearrangement. Computed kinetic isotope effects.