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

Previously, a mechanistic twist to the oxidation of imines using peracid had emerged. Time to see how substituents respond to this mechanism.

With X = NO₂ 100% oxaziridine and no nitrone is obtained experimentally; with X = NMe₂ , the population is inverted with nitrone as the dominant product at 78%.[1] Calculations (ωB97XD/Def2-TZVPP/SCRF=dichloromethane), data collection  DOI: 10.14469/hpc/1743[2] 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 = NO₂ (a ratio of 1024:1 in its favour) but reduced to 1.4 kcal/mol when  X = NMe₂.  This hardly changes when the acid is changed from ethanoic to mCPBA (meta-chloroperbenzoic acid), the oxidant actually used in the experiments.

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. 

These results show that our proposed mechanism can reproduce the selectivity for formation of oxaziridine when the aryl group bears X=NO₂  but misses the mark of predicting nitrone formation when X=NMe₂. Experimentally nitrone is favoured by ΔΔG₂₉₈ 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=NMe₂ 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.

References

1. D.R. Boyd, P.B. Coulter, N.D. Sharma, W. Jennings, and V.E. Wilson, "Normal, abnormal and pseudo-abnormal reaction pathways for the imine-peroxyacid reaction", Tetrahedron Letters, vol. 26, pp. 1673-1676, 1985. http://dx.doi.org/10.1016/S0040-4039(00)98582-4