The use of (S)-proline as a catalyst for intramolecular aldol reactions pioneered by Hajos, Parrish, Eder, Sauer and Wiechert paved the way for modern organo-catalysis, which earned MacMillan and List the Nobel Prize in Chemistry in 2021. The work reported herein shed light on mechanistic aspects regarding the "prototypal " H-P-E-S-W reaction that, up to date, are unclear. The DFT calculations determined i) the mechanism of the dehydration step of the ketol intermediate that proceeds via an E1cB (elimination, unimolecular, conjugate base) mechanism; ii) the rate-determining steps (RDS) of the H-P-E-S-W reaction that correspond to enamine formation and dehydration; iii) the catalytic role of the water molecule formed during the reaction, that behaves as a proton shuttle during the enamine and C-C bond formation and determines a significant lowering of the activation barriers.

Hajos-Parrish-Eder-Sauer-Wiechert reaction: The definitive reaction mechanism deciphered by DFT calculations

Edoardo Jun Mattioli;Matteo Calvaresi;Andrea Bottoni;Tainah Dorina Marforio
2022

Abstract

The use of (S)-proline as a catalyst for intramolecular aldol reactions pioneered by Hajos, Parrish, Eder, Sauer and Wiechert paved the way for modern organo-catalysis, which earned MacMillan and List the Nobel Prize in Chemistry in 2021. The work reported herein shed light on mechanistic aspects regarding the "prototypal " H-P-E-S-W reaction that, up to date, are unclear. The DFT calculations determined i) the mechanism of the dehydration step of the ketol intermediate that proceeds via an E1cB (elimination, unimolecular, conjugate base) mechanism; ii) the rate-determining steps (RDS) of the H-P-E-S-W reaction that correspond to enamine formation and dehydration; iii) the catalytic role of the water molecule formed during the reaction, that behaves as a proton shuttle during the enamine and C-C bond formation and determines a significant lowering of the activation barriers.
2022
Edoardo Jun Mattioli; Matteo Calvaresi; Andrea Bottoni; Tainah Dorina Marforio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/899246
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