Open AccessAccounting for Strong Ligand Sensitivity in Pd-Catalyzed α-Arylation of Enolates from Ketones, Esters, and Nitroalkanes
Author(s) -
Sergei Tcyrulnikov,
Marisa C. Kozlowski
Publication year - 2020
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.9b03203
Subject(s) - nitronate , chemistry , nitromethane , reactivity (psychology) , hsab theory , catalysis , reductive elimination , nitroalkene , computational chemistry , ligand (biochemistry) , transition state , combinatorial chemistry , reaction mechanism , nucleophile , medicinal chemistry , organic chemistry , photochemistry , nitro , enantioselective synthesis , receptor , medicine , biochemistry , alkyl , alternative medicine , pathology
The mechanism of the Pd-catalyzed α-arylation of three model enolates is studied focusing on an analysis of their very different reactivities. In particular, the low reactivity of nitronates under standard arylation conditions and their high sensitivity to the nature of catalytic systems are addressed. The three canonical steps for each of the reaction systems are examined, and key trends surrounding the stability of intermediates and transition states are delineated. A framework based on molecular orbital analyses and the hard-soft acid-base (HSAB) theory is advanced to explain the observed reactivity trends. The local softness of the enolates was found to be a key parameter controlling the energy of the enolate-catalyst complexes. The low reactivity of the nitroalkane enolates is attributed to slow reductive elimination, a consequence of the hard nature of the nitronate. Analysis of reactivity of nitromethane in α-arylation with Pd catalysts containing Buchwald ligands reveals destabilization of the L 2 Pd species as a major non-enolate-specific acceleration mechanism as well as less electron-rich ligands accelerating reductive elimination as a nitronate-specific mechanism. The corresponding energetics and feasibility that favor C-arylation versus O-arylation are outlined.