The Proline Enamine Formation Pathway Revisited in Dimethyl Sulfoxide: Rate Constants Determined via NMR

Abstract

Enamine catalysis is a fundamental activation mode in organocatalysis and can be successfully combined with other catalytic methods, e.g., photocatalysis. Recently, the elusive enamine intermediates were detected, and their stabilization modes were revealed. However, the formation pathway of this central organocatalytic intermediate is still a matter of dispute, and several mechanisms involving iminium and/or oxazolidinone are proposed. Here, the first experimentally determined rate constants and rates of enamine formation are presented using 1D selective exchange spectroscopy (EXSY) buildup curves and initial rate approximation. The trends of the enamine formation rates from exo-oxazolidinones and endo-oxazolidinones upon variation of the proline and water concentrations as well as the nucelophilic/basic properties of additives are investigated together with isomerization rates of the oxazolidinones. These first kinetic data of enamine formations in combination with theoretical calculations reveal the deprotonation of iminium intermediates as the dominant pathway in dimethyl sulfoxide (DMSO). The dominant enamine formation pathway varies according to the experimental conditions, e.g., the presence and strength of basic additives. The enamine formation is zero-order in proline and oxazolidinones, which excludes the direct deprotonation of oxazolidinones via E2 mechanism. The nucleophilicity of the additives influences only the isomerization rates of the oxazolidinones and not the enamine formation rates, which excludes a nucleophile-assisted anti elimination of oxazolidinones as a major enamine formation pathway.

Conformational Preferences in Small Peptide Models: The Relevance of cis/trans‐Conformations

“…The rate constants k were determined based on 1D‐selective NOESY/EXSY spectra in combination with the initial rate approximation as applied recently for investigations on the formation mechanism of the central organocatalytic enamine intermediate . This method is based on the work of Perrin and Dwyer and makes use of the NOESY experiment and the chemical exchange during the chosen mixing time τ m (for details, additional results applying a 2D NOESY approach as well as a rate constant cross check, see the Supporting Information).…”

“…[45] This methodi sb ased on the work of Perrin and Dwyer [46][47] and makes use of the NOESY experiment and the chemicale xchange during the chosen mixingt ime t m (for details, additional resultsa pplying a2 DN OESY approach as well as ar ate constant cross check, see the Supporting Information). [45] This methodi sb ased on the work of Perrin and Dwyer [46][47] and makes use of the NOESY experiment and the chemicale xchange during the chosen mixingt ime t m (for details, additional resultsa pplying a2 DN OESY approach as well as ar ate constant cross check, see the Supporting Information).…”

Nanocellulose enriches enantiomers in asymmetric aldol reactions

“…Albeit the reversibility, a critical control on the transition states can grant higher enantioselectivity within relatively short reaction time. 35,36 Fortunately, TOCNFs enabled faster reaction completion and the use of a lower concentration of (S)-proline. Furthermore, upon following the diastereoselectivity determined by SFC analysis until full conversion, no epimerization was detected as the dr stayed constant throughout the reaction (Fig.…”

From QCA (Quantum Cellular Automata) to Organocatalytic Reactions with Stabilized Carbenium Ions

“…When alcohols that can form quite reactive and electrophilic carbenium ions are employed, the formation of the carbenium ion becomes difficult, because they are forming a quite unstable and rapidly reactive carbenium ion. Not only water can compete for the reaction with the unstable carbenium ion, but it is quite important to mention that the concentration of enamine in catalytic reactions can be quite low,76 and other less nucleophilic species can be more effective, because their concentration is higher. On the other hand, when stable and isolable carbenium ions were tested (Scheme ), the reaction occurred without problems 77…”