Earlier I explored models for the heteroaromatic electrophilic protiodecarboxylation of an 3-substituted indole, focusing on the role of water as the proton transfer and delivery agent. Next, came models for both water and the general base catalysed ionization of indolinones. Here I explore general acid catalysis by evaluating the properties of two possible models for decarboxylation of 3-indole carboxylic acid, one involving proton transfer (PT) from neutral water in the presence of covalent un-ionized HCl (1) and one with PT from a protonated water resulting from ionised HCl (2).
The original study[1] noted that the rate of decarboxylation fitted well to the kinetic expression: rate = {a + b[L3O+]/(1 + c[L3O+])}[indole], where L can be H or D. Experimentally, [L3O+] is controlled by adding a strong general acid such as HCl, which when the appropriate number of water molecules are added[2] fully ionizes to H3O+.OH–. Now for B3LYP+D3/Def2-TZVPD/SCRF=water calculations:
Model | ΔG‡298 (0.044M) | DataDOIs | kH/kD[3] |
---|---|---|---|
1 | 27.4 | [4],‡[5],†[6],[7] | 5.69 |
2 | 16.8‡ (14.8)† | [5],[8],[9] | 2.45 |
‡Reactant as a non-ionised covalent HCl. †reactant as an isomeric ionized H3O+.Cl– beng 2.0 kcal/mol higher in energ within this solvation model. Note added in proof. A significantly lower form of the reactant has subsequently been located which increases the free energy barrier to 22.1 kcal (vis 22.0 actually measured!). Diacussion of this can be seen in the associated post here.
The transition state free energy however is ..
The clincher comes with calculation[3] of the kinetic isotope effects (KIE). For general acid catalysis, they were measured as kH/kD ~2.5.[1]
So we now have a model for the general acid catalysed decarboxylation of a 3-indole carboxylate which agrees with both the kinetic behaviours and the isotope effects measured for this reaction. Since the barrier is a relatively large one, proton tunnelling may play a lesser role in this interpretation, and the stage is set to use this model to e.g. explore how isotope effects are indeed influenced by tuning the reactivity using ring substitutents, the original purpose of my researches all those years ago. Perhaps the catch phrase I’ve started so I’ll start is now more apposite.
This post has been cross-posted in PDF format at Authorea.
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