Exploration of Ligand Effects, Substrate Effects and Reactor Effects on Macrocyclization via Ring-Closing Metathesis: A Rational Approach to Efficient Cyclization

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Title: Exploration of Ligand Effects, Substrate Effects and Reactor Effects on Macrocyclization via Ring-Closing Metathesis: A Rational Approach to Efficient Cyclization
Authors: Monfette, Sebastien
Date: 2011
Abstract: Olefin metathesis is credited with having transformed the way chemists think about the manipulation of C=C bonds, the success-story of which culminated in the highest of accolades to Schrock, Grubbs and Chauvin in 2005. It is, however, difficult to reconcile the groundbreaking effect that olefin metathesis had on organic synthesis, with its limited industrial applications. Nearly twenty years following the publication of the first well-defined Ru metathesis catalyst, the RCM reaction remains largely confined to the research setting. The low turnover numbers achieved by the Grubbs catalyst is the chief limiting factor preventing industrial uptake. Clearly, more efficient catalysts and reaction methodologies are needed to render RCM industrially viable. This thesis describes various approaches towards this goal. As macrocyclic targets are highly prized in the industry, a mechanistic investigation of their formation by the Grubbs and pseudohalide catalysts was performed. This study revealed that different reaction pathways are operative for different catalysts. While the first-generation catalyst effects RCM macrocyclization by the traditional, direct path, the second-generation catalysts afford macrocyclic products through a concentration dependent oligomerization-backbiting pathway. The second approach employs structure-activity relationship to examine the effect of the anionic ligands on metathesis activity. This study unambiguously showed, for the first time, that activity correlates with the electron-donating capacity of the anionic ligands. Therefore, incorporation of less electron-withdrawing anionic ligands was sought and the synthesis of nitrogen-bound pseudohalide catalysts was carried out. Gratifyingly, the isocyanate catalyst showed remarkable reactivity at room temperature. Polymers of well-defined chain length and low polydispersity could also be obtained with this catalyst, a task that has so far eluded all of the O-bound pseudohalide catalysts. Lastly, an examination of the effect of the reactor on RCM macrocyclization efficiency was performed. An appropriate choice of continuous-flow reactor resulted in the transformation of RCM efficiency. Much faster reaction kinetics were obtained using continuous-flow reactors. Furthermore, the attainable turnover numbers are one order of magnitude higher than those using the traditional batch setup.
URL: http://hdl.handle.net/10393/30147
http://dx.doi.org/10.20381/ruor-20098
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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