Posts Tagged ‘Nucleophile’

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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What is the approach trajectory of enhanced (super?) nucleophiles towards a carbonyl group?

Wednesday, May 11th, 2016

I have previously commented on the Bürgi–Dunitz angle, this being the preferred approach trajectory of a nucleophile towards the electrophilic carbon of a carbonyl group. Some special types of nucleophile such as hydrazines (R2N-NR2) are supposed to have enhanced reactivity[1] due to what might be described as buttressing of adjacent lone pairs. Here I focus in on how this might manifest by performing searches of the Cambridge structural database for intermolecular (non-bonded) interactions between X-Y nucleophiles (X,Y= N,O,S) and carbonyl compounds OC(NM)2.

The search query[2] is shown above and involves plotting the distance from the nucleophilic atom (N above) to the carbon of the carbonyl group. The carbon is defined as having 3-coordination, one of which is O=C and two non-metal attachments. The torsion is constrained to values of |70-110|° to ensure that the approach of the nucleophile is approximately perpendicular to the plane of the carbonyl in order to overlap with the π*-orbital as electrophile. The pairwise sums of van der Waals radii are NC, 3.25; OC, 3.22 and SC, 3.5Å and the plots show all contacts shorter than these. The results of the searches are shown below.

The general observation is that the red hotspots do tend to come at trajectory angles of <100° and many are <90° such as the X=Y=N or X=Y=S examples. Given that the original Bürgi–Dunitz hypothesis (actually based on a small number of molecules synthesized for the purpose) proposed rather larger angles (105±5°) corresponding to optimum alignment of the nucleophile with the carbonyl π*-orbital, we might speculate whether the use of enhanced nucleophiles is the reason for the apparent decrease in the angle. And if so, what the underlying reasons would be.

I also cannot help but observe that the term supernucleophile is quite rare in the literature; SciFinder gives only 45 hits, but most are about neither hydrazines nor peroxides. There are also some unusual nucleophile varieties such as Cob(I)alamin[3], of which there are probably insufficient examples to reflect in the crystal structure statistics shown above. Given the interest in superbases, the relative lack of examples of unusual supernucleophiles seems surprising.

References

  1. G. Klopman, K. Tsuda, J. Louis, and R. Davis, "Supernucleophiles—I", Tetrahedron, vol. 26, pp. 4549-4554, 1970. https://doi.org/10.1016/s0040-4020(01)93101-1
  2. H. Rzepa, "Crystal structure search using enhanced nucleophiles", 2016. https://doi.org/10.14469/hpc/487
  3. K.P. Jensen, "Electronic Structure of Cob(I)alamin:  The Story of an Unusual Nucleophile", The Journal of Physical Chemistry B, vol. 109, pp. 10505-10512, 2005. https://doi.org/10.1021/jp050802m

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