Internal Return of Carbon Dioxide in Decarboxylation: Catalysis of Separation and ¹²C/¹³C Kinetic Isotope Effects

Abstract

It has been proposed that the decarboxylation of mandelylthiamin, the adduct of benzoylformate and thiamin, is uniquely catalyzed by protonated pyridines through a preassociation mechanism in which proton transfer competes with the internal return of carbon dioxide. Application of this mechanism suggests that the observed primary (12)C/(13)C kinetic isotope effect in the absence of catalyst is reduced in magnitude because diffusion of carbon dioxide is partially rate-determining. Where proton transfer blocks the internal return of carbon dioxide, the separation of carbon dioxide is facilitated, and the observed isotope effect increases toward the intrinsic value for carbon-carbon bond breaking. Headspace analysis of carbon dioxide formed over the course of the reaction shows that protonated pyridine increases the magnitude of the observed (12)C/(13)C KIE, consistent with the proposed mechanism.

Catalyzing decarboxylation by taming carbon dioxide

“…Together, we developed methods to measure the CKIE under various conditions [48]. Mundle's results established that protonated pyridine does indeed produce an observable increase in the CKIE, consistent with this reaction model and its risky prediction [16]. Objections to this mechanism (based on computations) suggested in one instance that the role of pyridine is to lower the energy of the transition state without any comment on the critical issue of the effect of the catalyst of the magnitude of the CKIE [49].…”

“…However, our recent observations of catalysis of decarboxylation in solution suggested that the departure of CO 2 itself can be the source of low reactivity that is overcome by alternative pathways that promote separation of the products [12,13]. With that knowledge, we can consider previously undiscovered routes for catalyzing decarboxylation [12][13][14][15][16][17].…”

Observation of Thiamin-Bound Intermediates and Microscopic Rate Constants for Their Interconversion on 1-Deoxy-d-xylulose 5-Phosphate Synthase: 600-Fold Rate Acceleration of Pyruvate Decarboxylation by d-Glyceraldehyde-3-phosphate.

“…A likely explanation to consider for the effect of D-GAP is that decarboxylation is reversible 21–23 and CO2 release from the enzyme is potentiated by D-GAP binding. Several reports by Kluger et al .…”

Base-Catalyzed Decarboxylation of Mandelylthiamin: Direct Formation of Bicarbonate as an Alternative to Formation of CO2

“…It has been proposed that in a reaction that is slowed by recombination, a preassociated acid that quenches the carbanion (Scheme 1) increases the overall rate. 7 Recent reports of computational analyses dispute the possibility that the catalysis occurs by protonation in competition with recombination of CO 2 . 9,10 One of those reports concludes that the catalysis arises from stabilization of the transition state through complexation rather than proton transfer.…”