Ruthenium-Catalyzed Transformations of Alcohols: Mechanistic Investigations and Methodology Development

Ilya Makarov, Robert Madsen, Peter Fristrup

Research output: Book/ReportPh.D. thesis

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The mechanism of the ruthenium-catalyzed dehydrogenative synthesis of amides from alcohols and amines was studied in detail by employing the combination of experimental and theoretical techniques. The Hammett study revealed that a small positive charge is formed at the benzylic position
in the transition state of the turnover-determining step. The value of the kinetic isotope effect of 2.290.15 indicated that the C–H bond breakage is
not the rate-determining step, but that it is one of several slow steps in the catalytic cycle. Experiments with deuterium-labeled alcohols and amines
revealed that ruthenium-dihydride species are involved in the catalytic cycle. These experimental results were used in the dft/m06 computational study
and a plausible catalytic cycle was proposed. Both cis-dihydride and transdihydride intermediates were considered, but when the theoretical turnover
frequencies were obtained from the calculated energies, it was found that only the trans-dihydride pathway was in agreement with the experimentally
determined frequencies. The proposed catalytic cycle was used for an in silico search for more effective carbene ligands. The study showed that the ruthenium complexes with dimethoxyisopropylidene and pyridilidene ligands could be more active than RuCl2(IiPr)(p-cymene) used in the mechanistic investigation. Two analogs of the calculated complexes were synthesized but were not isolated in a pure form. The amidation reaction catalyzed by a mixture containing the
N-ethyl pyridilidene-substituted ruthenium complex afforded the amide in 38% yield. It indicated that in silico ligand screening might be used for catalyst
optimization if it is combined with a more comprehensive experimental study. An improved protocol was developed for the ruthenium-catalyzed dehydrogenative self-coupling of primary alcohols to give esters. Addition of 16.7 mol% of Mg3N2 to the reaction mixture gave esters from aliphatic alcohols
in similar yields but at lower temperature as compared with previously a reported catalytic system. This additive also suppressed the decarbonylation of
aromatic alcohols. A previously unknown ruthenium-catalyzed dehydrogenative Guerbet reaction with secondary alcohols to give ketones was discovered.
The reaction conditions were optimized and the scope and the limitations were studied. It was found that only acyclic 2-methyl carbinols and simple
cyclic alcohols underwent this transformation. It was shown that the reaction proceeded via the oxidation–aldol condensation–reduction pathway and that
the active ruthenium species was a dihydride During the external stay at Haldor Topsøe A/S, the transformation of acetaldehyde over zeolite-type heterogeneous catalysts was studied. It was shown that tin-Beta zeolite was only capable of producing crotonaldehyde in low yields. Several other heterogeneous catalysts were tested (Al-Beta, Ti-Beta, Sn-MCM-41, ts-1) but none of them demonstrated substantially higher activity in the studied transformation.
Original languageEnglish
PublisherDTU Chemical Engineering
Number of pages139
Publication statusPublished - 2013


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