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Mechanistic Investigation of the Ruthenium–N‐Heterocyclic‐Carbene‐Catalyzed Amidation of Amines with Alcohols
Author(s) -
Makarov Ilya S.,
Fristrup Peter,
Madsen Robert
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201202400
Subject(s) - chemistry , ruthenium , kinetic isotope effect , carbene , catalysis , catalytic cycle , deuterium , photochemistry , density functional theory , rate determining step , computational chemistry , medicinal chemistry , organic chemistry , physics , quantum mechanics
The mechanism of the ruthenium–N‐heterocyclic‐carbene‐catalyzed formation of amides from alcohols and amines was investigated by experimental techniques (Hammett studies, kinetic isotope effects) and by a computational study with dispersion‐corrected density functional theory (DFT/M06). The Hammett study indicated that a small positive charge builds‐up at the benzylic position in the transition state of the turnover‐limiting step. The kinetic isotope effect was determined to be 2.29(±0.15), which suggests that the breakage of the CH bond is not the rate‐limiting step, but that it is one of several slow steps in the catalytic cycle. Rapid scrambling of hydrogen and deuterium at the α position of the alcohol was observed with deuterium‐labeled substrates, which implies that the catalytically active species is a ruthenium dihydride. The experimental results were supported by the characterization of a plausible catalytic cycle by using DFT/M06. Both cis ‐dihydride and trans ‐dihydride intermediates were considered, but when the theoretical turnover frequencies (TOFs) were derived directly from the calculated DFT/M06 energies, we found that only the trans ‐dihydride pathway was in agreement with the experimentally determined TOFs.