Theoretical Studies on the Bifunctionality of Chiral Thiourea-Based Organocatalysts:  Competing Routes to C−C Bond Formation

Abstract

The mechanism of enantioselective Michael addition of acetylacetone to a nitroolefin catalyzed by a thiourea-based chiral bifunctional organocatalyst is investigated using density functional theory calculations. A systematic conformational analysis is presented for the catalyst, and it is shown that both substrates coordinate preferentially via bidentate hydrogen bonds. The deprotonation of the enol form of acetylacetone by the amine of the catalyst is found to occur easily, leading to an ion pair characterized by multiple H-bonds involving the thiourea unit as well. Two distinct reaction pathways are explored toward the formation of the Michael product that differ in the mode of electrophile activation. Both reaction channels are shown to be consistent with the notion of noncovalent organocatalysis in that the transition states leading to the Michael adduct are stabilized by extensive H-bonded networks. The comparison of the obtained energetics for the two pathways allows us to propose an alternative mechanistic rationale for asymmetric C-C bond forming reactions catalyzed by bifunctional thiourea derivatives. The origin of enantioselectivity in the investigated reaction is also discussed.

FT-IR, FT-Raman and ab-initio studies of 1,3-diphenyl thiourea

“…Theoretical study of the Hg 2+ recognition by 1,3-diphenylthiourea has been reported [2]. The mechanism of enantioselective Michael addition of acetylacetone to a nitroolefin catalyzed by a thiourea based chiral bifunctional organocatalyst is investigated using density functional theory calculations [3]. Yang et al [4] reported the structural and spectroscopic study of N-2-fluorobenzoyl-N'-4-methoxyphenyl thiourea.…”

Density Functional Theory Study of the Cinchona Thiourea‐ Catalyzed Henry Reaction: Mechanism and Enantioselectivity

“…[22] In the first, called Pathway A, the nucleophilic nitromethide anion is coordinated to the positivelycharged trialkylammonium, while the aldehyde electrophile is coordinated to the thiourea moiety ( Figure 4). In the second binding mode, called Pathway B, the opposite coordination pattern is found ( Figure 5).…”

Asymmetric organocatalytic Michael addition of Meldrum’s acid to nitroalkenes: probing the mechanism of bifunctional thiourea organocatalysts

“…12b The protonated tertiary amine then directs the nucleophile to attack from the less hindered face. In a theoretical study, Pápai and Sóos showed 13 that while calculations do support this, and also explain the preferred stereochemistry of the product, an opposite coordination scheme is not only possible, but in fact energetically slightly more favorable. …”