Origin of Chemoselectivity in N-Heterocyclic Carbene Catalyzed Cross-Benzoin Reactions: DFT and Experimental Insights

Abstract

An exploration into the origin of chemoselectivity in the NHC-catalyzed cross-benzoin reaction reveals several key factors governing the preferred pathway. In the first computational study to explore the cross-benzoin reaction, a piperidinone-derived triazolium catalyst produces kinetically controlled chemoselectivity. This is supported by (1)H NMR studies as well as a series of crossover experiments. Major contributors include the rapid and preferential formation of an NHC adduct with alkyl aldehydes, a rate-limiting carbon-carbon bond formation step benefiting from a stabilizing π-stacking/π-cation interaction, and steric penalties paid by competing pathways. The energy profile for the analogous pyrrolidinone-derived catalyst was found to be remarkably similar, despite experimental data showing that it is less chemoselective. The chemoselectivity could not be improved through kinetic control; however, equilibrating conditions show substantial preference for the same cross-benzoin product kinetically favored by the piperidinone-derived catalyst.

Insights into the Competing Mechanisms and Origin of Enantioselectivity for N-Heterocyclic Carbene-Catalyzed Reaction of Aldehyde with Enamide

“…5) are 2.21/2.17, 1.46/1.62 and 1.06/1.02 Å, respectively, indicating that carbon-carbon bond formation is more advanced than the proton migration. This observation is remarkably different from the hydroacylation reactions described on the above but similar with the previous reported aldehyde-aldehyde benzoin reactions14. In the formed intermediates t -M3S-b and t -M3R-b , C2‒C3 bond is formed and H2 atom is transferred to N3.…”

“…Particularly, the NHC-catalyzed Stetter reactions710111213, and the NHC-catalyzed aldehyde-aldehyde and aldehyde-ketone cross-benzoin reactions14151617 have been theoretically investigated, respectively. However, the hydroacylation mechanism involved in the reaction shown in Fig.…”

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

“…Tr aditionally,a za-Michael reactions have been catalyzed by aL UMO-lowering pathway.E ncouraged by our recent discovery of noncovalent catalysis with NHCs,wedecided to explore the orthogonal approach of the HOMO-raising activation of basic alkyl amines through hydrogen bonding. [24] We initially investigated ar eaction with benzylamine,a st his compound is considerably less basic than simple alkyl amines. (E)-1-Phenyl-1-trifluoromethyl-2-nitroethene (2a)w as used as the electrophile.T he aza-Michael reaction occurred without any catalyst at room temperature,and the racemic product was obtained quantitatively.…”

Insights into N‐Heterocyclic Carbene‐Catalyzed [4+2] Annulation Reaction of Enals with Nitroalkenes: Mechanisms, Origin of Chemo‐ and Stereoselectivity, and Role of Catalyst

“…Accompanied with the rapid experimentald evelopment of NHC catalysis, theoretical studies on NHC catalytic reactions have also been extensively reported by Bode, [15] Sunoj, [16] our group, [17] and others. [18] All these computational studies have greatly enhanced our understanding and insightsi nto the mechanism and stereoselectivity of NHC-catalyzed reaction processes.A sa ni mportant note, NHC catalytic reactions of enals are diverse due to the influence of catalysts, substrates, and additives on the protont ransfer process.T hus, it is necessary to carry out theoretical investigations for these novel organocatalytic reactions. To the best of our knowledge,t here are no computational studies on the NHC-catalyzed [4+ +2] reactions between enals and nitroalkenes.…”