In a previous post on the topic, I remarked how the regiospecific ethanolysis of propene epoxide[1] could be quickly and simply rationalised by inspecting the localized NBO orbital calculated for either the neutral or the protonated epoxide. This is an application of Hammond’s postulate[[2] in extrapolating the properties of a reactant to its reaction transition state. This approach implies that for acid-catalysed hydrolysis, the fully protonated epoxide is a good model for the subsequent transition state. But is this true? Can this postulate be tested? Here goes.
With no catalyst present, we know that the rate of hydrolysis is very slow[1], and that the major product (55%) is the 1-alkoxy-2-propanol, with the 2-alkoxy-1-propanol being the minor component (16%). As acid concentration increases, the amount of the latter eventually exceeds the former. The computed barriers (ωB97XD/6-311G(d,p)SCRF=methanol) for this mode (transition states 5 and 6) are ~29 kcal/mol, which pretty much matches the experimental observation (for ethanol). What does not match is the preference for nucleophilic attack at the least substituted carbon resulting in 1-alkoxy-2-propanol; instead the 2-alkoxy-1-propanol is predicted to have the lower free energy barrier of activation by 1.7 kcal/mol. This will need further investigation in a future post.
Property | 5, 2-alkoxy-1-propanol | 6, 1-alkoxy-2-propanol. |
ΔΔG‡, kcal/mol | 0.0 | +1.7 |
IRC animation | ||
IRC Energy | ||
IRC Gradients | ||
IRC | [3] | [4] |
What of the IRCs? Both isomers show an interesting dip in the gradient norms (at~-1.5 for 5 and +1.5 for 6), typical of a “hidden intermediate“. The geometry at this point (below) shows that the erstwhile epoxide bonds are largely formed/cleaved, and this has resulted in a zwitterionic intermediate attempting to form (the nucleophilic oxonium being +ve and the cleaved oxyanion -ve). Such species have no permanence however (not for even one molecular vibration), and are immediately destroyed by three more or less synchronous proton transfers (IRC -2.5 or +3.0). I would add that in many a text-book illustration of this process, this “hidden intermediate” would in fact be exposed as an explicit actual intermediate.
What happens when we replace one methanol in the above model with one molecule of trifluoracetic acid, resulting in transition states 1–4 (below).
Property | 1,2-alkoxy-1-propanol | 2, 1-alkoxy-2-propanol. |
ΔΔG‡ | 0.0 | +1.4 |
IRC animation | ||
IRC Energy | ||
IRC Gradients | ||
IRC | [5] | [6] |
Before moving on to the last models 7/8, I must mention the aspect of where the strong acid is located in the model. If it is located away from the epoxide oxygen, the IRC changes again, now revealing three hidden intermediates.
Property | 3, 2-alkoxy-1-propanol | 4, 1-alkoxy-2-propanol. |
ΔΔG‡ | 1.8 | +3.5 |
IRC animation | |
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IRC Energy | |
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IRC Gradients | |
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IRC | [7] | [8] |
The final model 7/8 tests what happens when that additional methanol is removed from the proton transfer sequence in 1-4. The smaller ring for the transition state induces an increase in the barrier from ~13 to ~20 kcal/mol; this model also naturally “absorbs” an addition methanol to decrease the free energy and mutate into 1-4. The preference for 7 over 8 is increased compared to the other models. The presence of two hidden intermediates in this model is particularly noticeable.
Property | 7, 2-alkoxy-1-propanol | 8, 1-alkoxy-2-propanol |
ΔΔG‡ | 0.0 | +3.5 |
IRC animation | |
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IRC Energy | |
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IRC Gradients | |
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To answer the question posed at the start of this post, in the IRC explorations above we see that in the presence of trifluoroacetic acid, the transition state is indeed preceded by a proton transfer. This reassures that Hammond’s principle can indeed be applied. The (relative) free energies of the acid catalysed transition state models used here all correctly predict the observed regiochemistry, but we still have to explore the base catalysed route. Watch this space.
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