The
mechanism of the Morita Baylis–Hillman reaction has
been heavily studied in the literature, and a long series of computational
studies have defined complete theoretical energy profiles in these
reactions. We employ here a combination of mechanistic probes, including
the observation of intermediates, the independent generation and partitioning
of intermediates, thermodynamic and kinetic measurements on the main
reaction and side reactions, isotopic incorporation from solvent,
and kinetic isotope effects, to define the mechanism and an experimental
mechanistic free-energy profile for a prototypical Morita Baylis–Hillman
reaction in methanol. The results are then used to critically evaluate
the ability of computations to predict the mechanism. The most notable
prediction of the many computational studies, that of a proton-shuttle
pathway, is refuted in favor of a simple but computationally intractable
acid–base mechanism. Computational predictions vary vastly,
and it is not clear that any significant accurate information that
was not already apparent from experiment could have been garnered
from computations. With care, entropy calculations are only a minor
contributor to the larger computational error, while literature entropy-correction
processes lead to absurd free-energy predictions. The computations
aid in interpreting observations but fail utterly as a replacement
for experiment.
Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.
Kinetic and mechanistic studies of the desymmetrization of benzhydrylamine using Pd/monoprotected amino acid ligands (Pd/MPAA) via C-H functionalization with molecular iodine provide mechanistic insight into the rate-determining step and the oxidation state of Pd in the C-H functionalization step. Enantiomeric excess is strikingly insensitive to temperature from ambient temperature up to over 70 °C, and reaction rate is insensitive to the electronic characteristics of the ligand's benzoyl protecting group. The reaction is highly robust with no evidence of catalyst deactivation. Intriguingly, C-H bond breaking does not occur prior to the addition of I to the reaction mixture. Electrochemical experiments demonstrate the viability of oxidative addition of I to Pd(II). Together with F NMR studies, these observations suggest that iodine oxidizes Pd prior to addition of the amine substrate. This work may lead to a better general understanding of the subtle variations in the reaction mechanisms for C-H functionalization reactions that may be extant for this ligand class depending on substrate, amino acid ligand and protecting group, and reaction conditions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.