Mechanistic Investigation of the Ruthenium–N-Heterocyclic-Carbene-Catalyzed Amidation of Amines with Alcohols

Authors

  • Ilya S. Makarov,

    1. Department of Chemistry, Building 201, Technical University of Denmark, 2800 Kgs. Lyngby (Denmark), Fax: (+45) 4593-3968
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  • Dr. Peter Fristrup,

    Corresponding author
    1. Department of Chemistry, Building 201, Technical University of Denmark, 2800 Kgs. Lyngby (Denmark), Fax: (+45) 4593-3968
    • Department of Chemistry, Building 201, Technical University of Denmark, 2800 Kgs. Lyngby (Denmark), Fax: (+45) 4593-3968
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  • Prof. Dr. Robert Madsen

    Corresponding author
    1. Department of Chemistry, Building 201, Technical University of Denmark, 2800 Kgs. Lyngby (Denmark), Fax: (+45) 4593-3968
    • Department of Chemistry, Building 201, Technical University of Denmark, 2800 Kgs. Lyngby (Denmark), Fax: (+45) 4593-3968
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Abstract

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 C[BOND]H 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.

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