Posts Tagged ‘Oxaziridine’

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

Sunday, October 9th, 2016

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

azir-x

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.

Substituents π σ
R=Me, X=NO2 -4.2 0.0 
R=Me, X=NMe2 -1.4 0.0
R=m-Cl-phenyl, X=NO2 -4.1 0.0 
R=m-Cl-phenyl, X=NMe2 -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. 

43

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. https://doi.org/10.1016/s0040-4039(00)98582-4
  2. H. Rzepa, "σ or π nucleophilic reactivity of imines", 2016. https://doi.org/10.14469/hpc/1743

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σ or π nucleophilic reactivity of imines? A mechanistic twist emerges.

Wednesday, September 28th, 2016

The story so far. Imines react with a peracid to form either a nitrone (σ-nucleophile) or an oxaziridine (π-nucleophile).[1] The balance between the two is on an experimental knife-edge, being strongly influenced by substituents on the imine. Modelling these reactions using the “normal” mechanism for peracid oxidation did not reproduce this knife-edge, with ΔΔG (π-σ) 16.2 kcal/mol being rather too far from a fine balance.

There are two general reasons why computational modelling using quantum mechanics may not match experimental outcome. Until perhaps 10 or so years ago, the culprits may often have been the approximations necessary to apply the theory, as bounded by the limitations of the CPU power of the then available computers to evaluate the associated equations. Nowadays, an equally likely explanation is that the molecular model for which these equations are solved is either wrong or maybe just incomplete. For an organic reaction, these models are initially set out by “arrow pushing” a possible mechanistic pathway. Such speculations have been a common feature of most new articles reporting the outcome of reaction experiments for perhaps 60 years now. It is now more common (but by no means universal) to augment this with a computational reality check. So previously, when I applied a reality check on the “standard” epoxidation mechanism, it did not pass the test.

So time to revise the mechanism, as per below. The difference is that the model includes an extra water molecule to facilitate proton transfers, with the imine now being protonated by the peracid to form a zwitterion, which collapses to an addition product and it is this species that rearranges to the final oxaziridine. Free energies relative to the reactant 1 are shown in red below.‡

azir

The IRC for 2 (TS) is shown below, being a proton transfer mediated by the transfer agent (water in this case, but it could be also peracid or eventually the product acid) to form a ion-pair.

2ts-irc1

4 (TS) shows the collapse of the ion-pair to form an addition product across the imine.

4ts-irc1

6 (TS, below) is the most interesting and also the high point on the free-energy pathway (i.e. the rate determining step). The addition product cyclises to an oxaziridine as induced by the nitrogen lone pair helping to evict the acetate anion. This is followed at IRC ~7 by a transfer of the N-H proton back to the carboxylic acid, again using water as a transfer agent with the whole being part of a concerted but asynchronous mechanistic step.

6ts-irc1

6g

Crucially, 6 (TS) is 23.4 kcal/mol below the oxaziridination transition state modelled without a prior proton transfer[2],[3] and even 7.6 kcal/mol below the transition state for nitrone formation.[4],[5]

So the original mechanism is now replaced by an alternative, which really only differs in the timing of how the acidic proton attached to the peracid responds to the process. By getting actively involved prior to the crucial reaction with the nitrogen lone pair of the imine, this proton enables a lower energy route to be established. We are now ready for the next “reality check” on these mechanisms, which are the effects of substituents on the imine. If these can be replicated, we can then really start to claim that computation has put the mechanism of this reaction onto a firmer footing than that based just on “arrow-pushing”.

‡Calculations (ωB97XD/Def2-TZVPP/SCRF=dichloromethane) for the species above are archived as a collection at DOI: 10.14469/hpc/1704[6] and individually at 1[7], 2 (TS)[8], 3[9], 4 (TS)[10], [11], 5[12], 6 (TS)[13],[14], 7[15].

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. https://doi.org/10.1016/s0040-4039(00)98582-4
  2. H. Rzepa, "Imine + peracetic acid, π attack + H2O, TS.", 2016. https://doi.org/10.14469/hpc/1698
  3. H. Rzepa, "Imine + peracetic acid, pi attack + H2O, TS. IRC", 2016. https://doi.org/10.14469/hpc/1701
  4. H. Rzepa, "Imine + peracetic acid,N attack + H2O, TS", 2016. https://doi.org/10.14469/hpc/1697
  5. H. Rzepa, "Imine + peracetic acid,N attack + H2O, TS IRC", 2016. https://doi.org/10.14469/hpc/1702
  6. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O reactant", 2016. https://doi.org/10.14469/hpc/1695
  7. H. Rzepa, "Imine + peracetic acid, π attack zwitterion + H2O", 2016. https://doi.org/10.14469/hpc/1703
  8. H. Rzepa, "Imine + peracetic acid, π attack zwitterion + H2O intermediate", 2016. https://doi.org/10.14469/hpc/1696
  9. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS", 2016. https://doi.org/10.14469/hpc/1692
  10. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS IRC", 2016. https://doi.org/10.14469/hpc/1700
  11. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, addition int", 2016. https://doi.org/10.14469/hpc/1690
  12. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS", 2016. https://doi.org/10.14469/hpc/1694
  13. H. Rzepa, "Imine + peracetic acid, π attack zwitterion + H2O TS IRC", 2016. https://doi.org/10.14469/hpc/1693
  14. H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, oxaziridine product", 2016. https://doi.org/10.14469/hpc/1691

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