Adaptive carbonyl umpolung involving a carbanionic carbene Breslow intermediate: an alternative mechanism for NHC-mediated organocatalysis

Abstract

The principal thermodynamic possibility for dynamic and adaptive NHC-mediated carbonyl umpolung, which enables the formation of a carbanionic carbene Breslow intermediate, has been theoretically demonstrated for the Benzoin condensation reaction.

Impact of Backbone Substitution on Organocatalytic Activity of Sterically Encumbered NHC in Benzoin Condensation

“…These experimental results suggest a significant decrease in the organocatalytic activity of highly sterically encumbered N-aryl NHC in benzoin condensation after backbone substitution. According to our previously reported mechanistic evidence, the benzoin condensation of furfural mediated by C4,5-unsubstituted imidazolidinyl carbenes may proceed via an adaptive dynamic mechanism involving both C2 and C4 positions of the imidazolium ring (Scheme 2) [23]. Deprotonating the C2-H position in the azolium cation with a base results in the formation of a normal (C2) carbene, with or without a significant energy barrier, depending on the specific base employed [23,24].…”

“…To prevent oxidation side processes during isolation, the conversions of aldehydes and yields of benzoin condensation products were assessed through 1 H nuclear magnetic resonance (NMR) analysis of crude reaction mixtures (isolated yields were not quantified). Results of reactions with IMes and IPr were obtained from reference [23]. The best results were observed for the reactions of IMes and IMes Me with furfural (entries 1, 3) or 5-methylfurfural (entries 7, 8) under ambient conditions with DBU as a base, resulting in >90% conversion and >50% yields of the corresponding C10 or C12 furoins.…”

“…Molecules 2024, 29, x FOR PEER REVIEW 2 of 8 aldehydes, which involves the generation of a C4-formed carbanionic carbene Breslow intermediate (CCBI) [23]. This mechanism is based on ambident reactivity of imidazole-2ylidenes by both C2 and C4 carbene positions, and was found to be particularly attractive for reactions involving aromatic aldehydes and sterically encumbered N-aryl-substituted NHC [23][24][25]. To further investigate the mechanism of carbonyl umpolung and steric influence of imidazolium backbone substitution, we performed comparative experimental and theoretical studies on the benzoin condensation reaction with aromatic aldehydes mediated by 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene (IMes) and 1,3-bis(2,6-diiso- While imidazole-2-ylidenes are well known as organocatalysts [3,5], the catalytic activity of C4,5-substituted imidazole-2-ylidenes has been investigated less often.…”

“…On the other hand, the decreased organocatalytic activity of some C4,5-substituted N-aryl imidazole-2-ylidenes have been revealed in benzoin condensation [22] and reaction of trans-cinnamaldehyde with parachlorobenzaldehyde [15]. In our previous work, we showed the thermodynamic possibility of a non-classical mechanism of NHC-mediated benzoin condensation of aromatic aldehydes, which involves the generation of a C4-formed carbanionic carbene Breslow intermediate (CCBI) [23]. This mechanism is based on ambident reactivity of imidazole-2-ylidenes by both C2 and C4 carbene positions, and was found to be particularly attractive for reactions involving aromatic aldehydes and sterically encumbered N-aryl-substituted NHC [23][24][25].…”

“…In our previous work, we showed the thermodynamic possibility of a non-classical mechanism of NHC-mediated benzoin condensation of aromatic aldehydes, which involves the generation of a C4-formed carbanionic carbene Breslow intermediate (CCBI) [23]. This mechanism is based on ambident reactivity of imidazole-2-ylidenes by both C2 and C4 carbene positions, and was found to be particularly attractive for reactions involving aromatic aldehydes and sterically encumbered N-aryl-substituted NHC [23][24][25].…”