On the Organocatalytic
Activity of N-Heterocyclic
Carbenes: Role of Sulfur in Thiamine
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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 decouplinga reverse benzoin condensationthis
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