Rate-determining processes in acid-catalyzed decarboxylation reactions

The acid-catalyzed decarboxylation reactions of indole- and pyrrole-carboxylic acids require the addition of one equivalent of water to the carboxyl group and a proton to the heterocyclic ring carbon at the position alpha to the carboxyl. Where alpha-protonation is thermodynamically favoured over beta-protonation, the magnitude of the observed 12 C/13C kinetic isotope effect (CKIE) is greater than where the beta-position is protonated. This can be understood in terms of a mechanism involving a protonated hydrated precursor to carbon-carbon bond cleavage, where the difference in energy of intermediates and transition states control the proportioning of the intermediates. The intrinsic CKIE on the carbon-carbon bond-breaking step that produces protonated carbonic acid (PCA) is independent of the site of protonation. The interpretation of the observed CKIEs can be generalized based on intermediates from isomeric carboxylic acids whose energetics vary predictably with their sites of protonation. The relative free energy barriers to reversion and formation of PCA control the magnitude of the observed CKIEs and correlate with reactivity. The reported data implicate the formation of PCA as the initial product of carbon-carbon bond cleavage. Application of the principle of microscopic reversibility implies that electrophilic aromatic substitution based on PCA should be an accessible route to carboxylation of aromatic substrates. Over the course of the project, new methods were developed for the simultaneous pressure detection and mass spectral analysis of carbon dioxide released as a final product. Specifically, headspace gas analysis and compound-specific isotope analysis of carbon dioxide have been coupled as a result. The evaluation for new decarboxylation mechanisms in general has led to a clearer understanding of how the intervention of hydrated intermediates leads to formation of PCA and its subsequent rapid conversion to carbon dioxide.