Interconversion and Interception of Reactive Intermediates Using H2

Abstract

This dissertation describes the advances in hydrogen transfer catalysis with nitrogen-based substrates using ruthenium pincer catalysts. Compared to C–O bonds, amines, imines, and nitriles are difficult substrates for (de)hydrogenation reactions. The high Lewis basicity of nitrogen often encourages the deactivation or inhibition of a transition-metal catalyst and can promote undesirable side reactions between the organic intermediates. Because of these challenges, the mechanistic details and catalyst requirements for hydrogen transfer across C–N bonds are not well-understood. The ruthenium-pincer catalyst, HRu(bMepi)(PPh3)2 (1, bMepi = 1,3-bis(6’-methyl-2’-pyridylimino)isoindoline) provides critical details needed for developing new synthetic strategies based on nitrogen-containing substrates by capturing snapshots of amine, imine, and nitrile intermediates during hydrogen transfer. Primary amines undergo dehydrogenation catalyzed by 1 to selectively form nitriles with the release of 2 equivalents of H2. Computational, kinetic, and spectroscopic experiments elucidate an inner-sphere dehydrogenation mechanism with a high kinetic barrier to form a Ru–(2-H2) intermediate via H+ transfer between a Ru–NH2 to Ru–H unit (ΔG‡ = 35(2) kcal/mol for octylamine). The unusual selectivity for nitrile products, rather than secondary amines or imines, depends on a fast second dehydrogenation event and a high binding affinity of imino groups to Ru. Additionally, bulky ortho-pyridyl substituents on the pincer ligand are required to stabilize high energy 5-coordinate Ru-amido intermediates. This mechanism is compared to analogous hydrogen transfer reactions of alcohols, revealing the fundamental differences between substrate classes despite similar elementary steps. The new chemical knowledge gained from our mechanistic analysis was further applied to develop new hydrogen transfer methodologies for amines and nitriles. The reversibility of hydrogen transfer and high binding affinity of nitrogen was exploited in a new protocol for the stereoretentive H/D exchange of primary amines using D2O. While 1 promotes the H/D exchange of (S)-1-phenylethylamine with 90% ee, the cationic derivative, [Ru(bMepiMe)(PPh3)OTf]OTf, facilitates H/D exchange with complete stereoretention. The binding affinity of a prochiral imino intermediate increases with the increased positive charge on Ru. In addition to the high binding affinity of a Ru-imino intermediate, stereospecific coordination of the chiral amine to Ru and a fast H/D exchange from Ru–H are hypothesized to promote stereoretentive H/D exchange. These studies led to the successful labeling of primary amines with high deuterium content (70-99% D) and complete stereoretention (99% ee) at the α-CH position. Finally, α,β-unsaturated nitriles are intercepted through hydride insertion to produce novel Ru-ketenimine intermediates. X-ray crystallography of a Ru-ketenimine derived from α-phenylcinnamonitrile reveals a highly unusual bent geometry with Ru–N–C of 141°. Spectroscopic and computational analysis suggest that subsequent reactivity is dictated by the electronic environment of the α,β-unsaturated nitrile, which influence the nucleophilic and electrophilic character of the –C2=C1=N heterocumulene group. To regenerate the Ru–H intermediate and enable catalytic reactivity, electrophilic and nucleophilic additions were performed under an H2 atmosphere. Under these conditions, the hydrogenation, hydroboration, hydroacylation, and hydrosilylation of α,β-unsaturated nitriles via ketenimine intermediates are explored.