Imperial College London

Henry Rzepa

[Previously](http://www.ch.imperial.ac.uk/rzepa/blog/?p=16902), a
mechanistic twist to the oxidation of imines using peracid had emerged.
Time to see how substituents respond to this mechanism.

[![azir-x](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/10/azir-X.svg){.aligncenter
.size-large .wp-image-16944 decoding="async"
width="350"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/10/azir-X.svg)

With X = NO~2~ 100% oxaziridine and no nitrone is obtained
experimentally; with X = NMe~2 ~, the population is inverted with
nitrone as the dominant product
at 78%.\[cite\]10.1016/S0040-4039(00)98582-4\[/cite\] Calculations
(ωB97XD/Def2-TZVPP/SCRF=dichloromethane), data collection  DOI:
[10.14469/hpc/1743](http://doi.org/10.14469/hpc/1743)\[cite\]10.14469/hpc/1743\[/cite\]
are summarised in the table. The initial model employs the simpler
peracetic acid as oxidant (R=Me) and we see here a computed preference
of 4.2 kcal/mol for oxiziridine when the aryl substituent X = NO~2 ~(a
ratio of 1024:1 in its favour) but reduced to 1.4 kcal/mol when  X
= NMe~2~.  This hardly changes when the acid is changed from ethanoic to
mCPBA (meta-chloroperbenzoic acid), the oxidant actually used in the
experiments.

|                         |      |      |
|-------------------------|------|------|
| Substituents            | π    | σ    |
| R=Me, X=NO~2~           | -4.2 | 0.0  |
| R=Me, X=NMe~2~          | -1.4 | 0.0  |
| R=m-Cl-phenyl, X=NO~2~  | -4.1 | 0.0  |
| R=m-Cl-phenyl, X=NMe~2~ | -1.3 | 0.0  |

You can see from the transition state structures that π attack is helped
by stacking between the aryl face of the m-chloroperbenzoic acid and the
aryl group on the imine, whereas σ is not. 

![4](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/10/4-1024x855.jpg){decoding="async"
width="220"}![3](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/10/3-1024x511.jpg){decoding="async"
width="220"}

These results show that our proposed mechanism can reproduce the
selectivity for formation of oxaziridine when the aryl group
bears X=NO~2 ~ but misses the mark of predicting nitrone formation
when X=NMe~2~. Experimentally nitrone is favoured by ΔΔG~298~ 0.75
kcal/mol, whereas the calculation disfavours this by -1.3 kcal/mol. Is
this discrepancy enough to sink this mechanistic model?  Or might yet
another variation on the mechanism, such shifting the proton from
peracid to the X=NMe~2 ~do the trick? 

What  I have tried to show here is how one can iterate towards a
realistic mechanism by gradually refining the models so that more and
more experimental observations are correctly predicted.  Sometimes of
course, it might be the experiment itself that has to be repeated and
refined, although we have not quite reached that point yet with this
example.

 

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Previously, a mechanistic twist to the oxidation of imines using peracid had emerged. Time to see how substituents respond to this mechanism. With X = NO
<sub>
 2
</sub>
100% oxaziridine and no nitrone is obtained experimentally;

Messaggi di Rogue Scholar

σ or π nucleophilic reactivity of imines? A mechanistic reality check using substituents.