Ruthenium-Catalyzed Amidation of Alcohols

The next example is concerned with the oxidative amidation of benzylic alcohols. This reaction has significant synthetic potential, as amide bonds are one of the most abundant and most important classes of chemical bonds in nature and in the chemical industry. It is, therefore, of considerable interest to understand the mechanism of this transformation in order to improve not just the selectivity and the yield, but also the substrate scope, catalyst loading, and catalyst lifetime. 

NMR studies revealed the presence of palladium hydride complexes as well as complexes with and without phosphine. They furthermore showed rapid release of -cymene from palladium indicating that the active catalyst most likely does not include p-cymene. 

The previously mentioned isotope scrambling is endothermic for pathway a and exothermic for pathway b, which makes pathway b the more likely scenario. Another piece of computational evidence supporting pathway b is the fact that the rate calculated from the energetic span of the whole catalytic cycle is close to 

The calculated KIE for the reaction with benzylamine of 3.78 does not fit well with the experimentally determined value of 2.29. The authors explain this discrepancy with the fact that different amines were used in the experimental and computational parts and propose that the a substituent on the amine has significant influence on the observed KIE. Furthermore, KIE for the related ruthenium-catalyzed hydrogenation vary significantly depending on the choice of solvent and 

Overall, the experimental and theoretical results do not match perfectly, but the experimental evidence is stUl able to sufficiently validate the computational results. This study provides insight into the mechanism of the ruthenium-catalyzed oxidative amidation of alcohols that may, as the authors suggest, be used to perform in silico ligand studies in the future. 

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Scheme 8.12 Proposed catalytic cycles for the ruthenium-catalyzed amidation of alcohols.

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