I mentioned in the last post that one can try to predict the outcome of electrophilic aromatic substitution by approximating the properties of the transition state from those of either the reactant or the (presumed Wheland) intermediate by invoking Hammond’s postulate[1]. A third option is readily available nowadays; calculate the transition state directly. Here are the results of exploring this third variation.
I am going to use the model shown above, which is actually the relatively unusual electrophile nitrosium trifluoracetate. My reasons for this strange selection are:
The mechanism can either be a more conventional stepwise nucleophilic/electrophilic push-pull (blue + green arrows) or it has the potential of avoiding the formation of any (Wheland) intermediate by instead being a concerted (red + green arrows) process. We will leave the detailed timing of these arrows to the quantum mechanics to settle. The results (ωB97XD/6-311G(d,p)/SCRF=dichloromethane) are as follows (relative energies in kcal/mol).
Substitution at the nitrogen (1-position) is the clear winner in terms of the free energy of activation (ΔG‡, kinetic control) but the clear looser in terms of the free energy of reaction (thermodynamic control).
Position | Transition state | Product |
1 | -4.93 | 10.62 |
2 | 1.96 | 4.86 |
3 | 0.0 | 0.0 |
Time to take a detailed look at the three transition states located and their intrinsic reaction coordinates.
The actual outcome (3-position) emerges as the clear thermodynamic winner, but 1-substitution as the (reversible?) kinetic preference. This does raise one intriguing question: might electrophilic substitution of indole in the 3-position actually arise from this initial kinetically controlled 1-substitution followed by some form of rearrangement to the most stable thermodynamic 3-product? I have not identified such a route, which may well be mediated by the position of the trifluoracetate component (and the nature of the solvent and its ability to stabilize ion-pairs).
I am however encouraged that this exploration of transition states has if nothing else introduced some new ideas. I do worry that much organic chemistry continues to be taught against the “text-book” interpretations, and we do need to identify conduits for new ideas to ensure that the core of organic chemistry continues to be vibrant.
Postscript: If you inspect the tail end of the IRC for the 3-indole substitution, you will see the formation of trifluoroacetic acid by proton abstraction from the 3-position. This tail involves a gradual drifting of this acid (IRC ~-10 to -18) to take up a new position over the 4-carbon of the indole by the formation of a π-facial bond. This more or less coincides with the shape of the molecular electrostatic potential of the product in that region (below).
‡ A concerted process for aromatic electrophilic substitution of benzene by the nitrosonium cation has been reported[2], but here the proton transfer occurs AFTER the C-N=O bond is formed.
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