On the Organocatalytic Activity of N-Heterocyclic Carbenes: Role of Sulfur in Thiamine

Abstract

The reaction energy profiles of the benzoin condensation from three aldehydes catalyzed by imidazol-2-ylidene, triazol-3-ylidene, and thiazol-2-ylidene have been investigated computationally. The barriers for all steps of all investigated reactions have been found to be low enough to indicate the viability of the mechanism proposed by Breslow in the 1950s. The most remarkable difference in the catalytic cycles has been the increased stability of the Breslow intermediate in case of thiazol-2-ylidene (by ca. 10 kcal/mol) compared to the other two carbenes, which results in lower energy for the coupling of the second aldehyde molecule, thus, increasing the reversibility of the reaction. Since the analogous transketolase reaction, being involved in the carbohydrate metabolism of many organisms, requires an initial decoupling-a reverse benzoin condensation-this difference provides a reasonable explanation for the presence of a thiazolium ring in thiamine instead of the otherwise generally more available imidazole derivatives. The "resting intermediate" found by Berkessel and co-workers for a triazole-based catalyst was found more stable than the Breslow intermediate for all of the systems investigated. The (gas phase) proton affinities of several carbenes were compared, the relative trends being in agreement with the available (in aqueous solution) data. The hydrolytic ring-opening reaction of the thiazole-based carbene was shown to be different from that of imidazole-2-ylidenes.

Reprint of “The benzoin condensation: Charge tagging of the catalyst allows for tracking by mass spectrometry”

“…4). The calculated high stability of 2c is consistent with the isolation of a ketone structure in benzoin condensation studies by Berkessel and co-workers in 2010 [28,50,53,54].…”

“…Other possible structures include the ketone 2c and the epoxide 2d (Fig. 2) [28,30,41,[50][51][52][53][54]. MS/MS of m/z 326 yields m/z 311 (loss of CH 3 • ) and m/z 220 (catalyst 1) as the two strongest signals, with the m/z 311 signal being more than twice that of m/z 220.…”

Systematic Strategy for Designing Immidazolium Containing Precursors To Produce N-Heterocyclic Carbenes: A DFT Study

“…PA value is directly proportional to basicity and it has strong influence on stability of cationic NHC precursors. 40 It means that the cationic NHC precursors are more stable as their PA increase, whereas it is hard to generate their neutral carbenes.…”

Advances in the Knowledge of N-Heterocyclic Carbenes Properties. The Backing of the Electrochemical Investigation

“…In fact, the enzyme transketolase, in the presence of vitamin B 1 (thiamine), catalyzes (via a nucleophilic acylation reaction) the transfer of a two-carbon unit from a carbohydrate to another (transketolase process). The transformation of thiamine into its active carbene suggests a Benzoin-like mechanism [19].…”

“… the effective presence of dimeric structures instead of (or in addition to) free NHC;  the influence of the dimeric partner on the NHC lone pair availability (i.e., on the catalytic efficiency) [16,19,[82][83][84];  the higher stability of the dimeric structure than that of free NHC; and  the nature of the "effective" catalyst, i.e., the attack to the active site of the substrate is carried out by free NHC (being the dimeric structure a precursor of free NHC) or by the dimer? In fact, a direct interaction between substrate and dimeric structure could not be rejected.…”