Posts Tagged ‘Rearrangement reactions’

Epoxidation of ethene: a new substituent twist.

Friday, December 21st, 2018

Five years back, I speculated about the mechanism of the epoxidation of ethene by a peracid, concluding that kinetic isotope effects provided interesting evidence that this mechanism is highly asynchronous and involves a so-called “hidden intermediate”. Here I revisit this reaction in which a small change is applied to the atoms involved.

Below are two representations of the mechanism. The synchronous mechanism involves five “curly arrows”, two of which are involved in forming a bond between oxygen and carbon, and three of which transfer a proton to the group X (X=O). The second variation asynchronously stops at the half way stage to form a pseudo ion-pair (the “hidden intermediate”) and the proton transfer only occurs in the second stage. If the ethene is substituted with deuterium, experimentally an inverse kinetic isotope effect is observed, which provides strong evidence that at the transition state, no proton transfer is occurring

Before I go on, I should say that you will not find the mechanism as shown in either variation above in very many text books, which tend to practice “curly arrow economy” by employing only four arrows. I will not pursue this aspect here, except to note that as drawn above, the synchronous mechanism resembles that of a pericyclic reaction in a variation known as coarctate, as I noted in the original post (DOI: 10.14469/hpc/4807).

Now I introduce a veritable variation into this reaction, known as Payne epoxidation[1],† which replaces the peracid with a reagent generated by adding hydrogen peroxide to a nitrile to generate a transient species which can be represented by X=NH above. How does this change things? The model below also uses propene rather than ethene (M062X/Def2-TZVPPD/SCRF=dichloromethane).‡ This transition state (ΔG298 31.3 kcal/mol) shows two C-O bond formations, and as before the proton is clearly not yet transferred to the nitrogen (X=NH). Because of this asynchrony, the reaction could also be called a coarctate pseudo-pericyclic reaction.

Asynchronous concerted mechanism. Click for 3D

However, the proton transfer is nonetheless part of a concerted mechanism, as shown by the IRC profile.

The gradient norm most clearly shows the “hidden ion-pair intermediate” at IRC = -1, and the proton transfer only occurs after this point is passed.

This is even more spectacularly illustrated with a plot of dipole moment along the IRC;

In truth, no real differences are yet revealed between the Payne reagent and the peracid. In fact, this is a real surprise, since the NH of the Payne reagent should be very much more basic than the carbonyl oxygen of the peracid. But more exploration of the potential energy surface reveals another transition state!

Stepwise mechanism. Click for 3D

This is seen forming the two C-O bonds AFTER the proton transfer from oxygen to nitrogen. It is 4.2 kcal/mol lower than the first transition state, which corresponds to the scheme below.

The new ion-pair shown above is 7.1 kcal/mol higher than the previous reactant, but is so much more basic than before that the overall activation energy is indeed lowered. Two distinctly separate IRCs can be constructed for this alternative, the first a pure proton transfer (not shown) and the second a pure C-O bond forming process (below). This second step is both concerted and almost purely synchronous.

So now we see how a small change to the reactant molecules (X=O to X=NH) can induce a reaction for which two quite different mechanisms can operate, an asynchronous one albeit with a hidden intermediate and a fully stepwise one in which a quite different, but this time real, intermediate is involved. Nevertheless for both the peracid mechanism and the peroxyimine variation shown here, the proton transfer is NOT involved in the rate limiting step. So for this variation too, inverse kinetic isotope effects would be expected.

‡FAIR data for the calculations at DOI: 10.14469/hpc/4909 †Thanks Ed for pointing this out.

References

  1. G.B. PAYNE, P.H. DEMING, and P.H. WILLIAMS, "Reactions of Hydrogen Peroxide. VII. Alkali-Catalyzed Epoxidation and Oxidation Using a Nitrile as Co-reactant", The Journal of Organic Chemistry, vol. 26, pp. 659-663, 1961. https://doi.org/10.1021/jo01062a004

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A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?

Saturday, November 28th, 2015

In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does not happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation has to say about what does (or might) not happen.

TD

I start with posing the question what does the chloride counter-ion do? If you are aware of the literature on computational reaction mechanisms, you may note that where ionic species are involved, one of the ions is often excluded from the calculations. Here for example, the pertinent reacting species is a diazonium cation, but the anion would likely not be mentioned, and the calculation would be performed as a charged cation (the physically unrealistic charge=1 in the input file!). This is because of an awkward difficulty with ion-pairs. There is no formal bond between the two charged fragments (unless a zwitterion) and so it is not entirely obvious quite where to place the counter-ion. In the diagram above, position 1 is where it was in my first exploration, but with knowledge that it might form a hydrogen bond to an acidic hydrogen, one could also perhaps place it into positions 2 or 3. In 2, as shown by the blue arrows and product above, an entirely different reaction occurs known as the Grob fragmentation.[1] In fact as a di-carbonyl compound, it can then participate in an acid-catalysed aldol condensation and this can lead to the same product as the original Tiffeneau-Demjanov rearrangement, albeit with loss of stereochemical integrity. So it might be worth effort in explaining whether this alternative is likely (in other words how robust the likely stereochemical integrity of the product is).

System Relative TS free energy TS Dipole moment DataDOI
1 0.0 17.7 [2]
2 1.4 24.2 [3]
3 3.7 29.3 [4]

The energies of the three located transition states increase with the dipole moment; as the counter-ion moves further from the positive charge, its position becomes less stable. Still, route 2 is not that much higher in energy. Time for an IRC (intrinsic reaction coordinate) to explore what actually does happen during route 2, the possible Grob rearrangement.

grob1

The reaction animation above shows the required Grob characteristic, the green bond breaking. But instead of the OH then de-protonating, the hydrogen stays in place and instead the Tiffeneau-Demjanov migration takes place. This will require removal of a different proton and indeed in the latter stages, the chloride anion starts off in its determined journey to do so.

GrobDM

The variation in dipole moment as the reaction proceeds is fascinating. At IRC -6, it reaches a minimum, but then reverses itself in hunt of a better way of reducing the dipole moment.

What about 3? This is slightly artificial, since the real system has a methoxy group here, which would inhibit this route. One can still learn chemistry though. The hydrogen bond formed from chloride to the OH encourages the anomeric effect to form a partial oxy-anion, which in turn encourages the red bond to break rather than the green one. But in fact no complete proton transfer happens, and the reaction reaches a non-productive cul-de-sac. 

Alt1

So, to conclude, there is no Grob fragmentation! Instead, a slightly confused Tiffeneau-Demjanov migration occurs in a rather more roundabout manner than previously. We have explored here just TWO reaction trajectories. A more statistical exploration of the trajectory landscape will give us a more complete picture, but I rather fancy that would be very well above the call of duty required to answer a stereochemical problem!

References

  1. C.A. Grob, and W. Baumann, "Die 1,4‐Eliminierung unter Fragmentierung", Helvetica Chimica Acta, vol. 38, pp. 594-610, 1955. https://doi.org/10.1002/hlca.19550380306
  2. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191653
  3. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191654
  4. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191655

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