Reactivity and Enantioselectivity in NHC Organocatalysis Provide Evidence for the Complex Role of Modifications at the Secondary Sphere

Zayed Alassad, Ashim Nandi, Sebastian Kozuch, Anat Milo

Research output: Contribution to journalArticlepeer-review

Abstract

Secondary-sphere interactions are often harnessed to control reactivity and selectivity in organometallic and enzymatic catalysis. Yet, such strategies have only recently been explicitly applied in the context of organocatalytic systems. Although increased stability, reproducibility, and selectivity were obtained in previous work using this approach, the precise mechanistic pathway promoted by secondary-sphere modification in organocatalysis remained unclear. Herein, we report a comprehensive mechanistic study on the origin of the unique reactivity patterns and stereocontrol observed with boronic acids (BAs) as secondary-sphere modifiers of N-heterocyclic carbene (NHC) organocatalysts. Kinetic experiments revealed partial order in catalyst upon the addition of BA and unusual preactivation behavior, indicating the presence of stable off-cycle catalyst aggregation and BA-base adducts. These hypotheses were supported both by computations and by a series of NMR and nonlinear effect experiments. Furthermore, computations indicated a rate-limiting, water-assisted hydrogen atom transfer mechanism. This finding led to a considerable enhancement in the experimental reaction rate while maintaining excellent enantioselectivity by adding catalytic amounts of water. Finally, computations and racemization experiments uncovered an uncommon Curtin-Hammett-controlled enantioselectivity in the presence of secondary-sphere modifiers.

Original languageEnglish
Pages (from-to)89-98
Number of pages10
JournalJournal of the American Chemical Society
Volume145
Issue number1
DOIs
StatePublished - 11 Jan 2023

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)
  • Biochemistry
  • Colloid and Surface Chemistry

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