Dynamic Ligand Exchange as a Mechanistic Probe in Pd-Catalyzed Enantioselective C–H Functionalization Reactions Using Monoprotected Amino Acid Ligands

Abstract

A new tool for probing enantioselective reaction mechanisms is introduced. Monitoring the temporal change in product enantiomeric excess after addition of the opposite enantiomer of the ligand during the reaction provides a means of probing dynamic ligand exchange in enantioselective C-H iodination catalyzed by Pd with monoprotected amino acid ligands (MPAAs). This work has general potential to provide insights about the dynamics of catalyst and ligand molecularity and exchange.

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid Accelerated Enantioselective C-H Functionalization

“…22 Despite the many exciting developments in Pd-MPAA methodology and several experimental and computational studies aimed at understanding these reactions, the structures of Pd-MPAA catalysts remains unclear in most cases. In a notable exception to this trend, a recent kinetic, spectroscopic, and computational study of MPAA-accelerated C-H iodination reactions 23,24 provided experimental data consistent with a previously reported [25][26][27][28] structural model featuring mono-nuclear Pd intermediates with di-anionic κ 2 -(N,O)-bound MPAA ligands ( Figure 2B). Given the general structural ambiguity surrounding Pd-MPAA catalysis, mechanistic models generally defer to the widely-held notion that MPAA ligands coordinate mono-palladium species by di-or mono-anionic chelation (Figure 2A and B, respectively).…”

“…Ligand exchange was confirmed under catalytic conditions by monitoring the rapid change in ee when a reaction is initiated with D-MPAA and subsequently spiked with L-MPAA (SI Figure 33). 24 Together, these studies highlighted the utility of dmaf olefination for kinetic analysis, but catalyst degradation observed during reaction progress kinetic analysis 69 necessitated the use of initial rates (SI Figure 31). 70 Initial rate data were used to determine the order of each reaction component in dmaf olefination, and thus the extent to which each component contributes to the rate of Pd-MPAA turnover in this reaction ( Figure 7D-G).…”

Computational exploration of Pd‐catalyzed C–H bond activation reactions

“…It can provide useful mechanistic information such as the rate‐limiting step and active palladium catalyst species (monomeric or dimeric Pd), and can also provide a diagnostic for either palladium catalyst deactivation or product inhibition. Combining kinetic experiments with spectroscopic characterization, such as nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, mass spectrometry (MS), and DFT computations provides insights for comprehensive mechanistic understanding of the catalytic system …”

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid-Accelerated Enantioselective C–H Functionalization

“…The bidentate model was supported by the observation that N -methyl ligands afforded minimal enantioinduction . The hypothesis that bidentate MPAA coordination could enable rate acceleration and stereoinduction was subsequently corroborated by DFT calculations, − observation of Pd–MPAA ions via high-resolution mass spectrometry, − first-order dependence on total palladium in steady-state kinetics, , and a lack of nonlinear effects (NLE) in asymmetric reactions. , As indicated by its frequent reproduction in review literature, ,,,− the bidentate model has been widely adopted as a general mechanism to rationalize rate acceleration and stereocontrol in Pd–MPAA catalysis.…”