Olefin Ring‐closing Metathesis under Spatial Confinement and Continuous Flow

Abstract

We report on the use of a 2 nd -generation Hoveyda-Grubbs-type catalyst immobilized inside mesoporous silica for the application in selective macro(mono)cyclization (MMC) of an α,ω-diene under spatially confined and continuous-flow conditions. Reactions carried out with different flow rates allow for variations in residence time; conversion and MMC selectivity can be determined for well-defined reaction times. Analysis of the reaction mixtures obtained for different reaction times and temperatures in a single flow experiment by NMR and MALDI-TOF-MS allows to address confinement effects and to determine olefin metathesis pathways. These investigations revealed that ring-chain equilibria are quickly established but substantially affected by residence time and flow, allowing for the determination of conditions under which MMC selectivity reaches a maximum. In contrast to reactions carried out in solution, in which oligomers up to the hexamer were observed, MMC under confinement predominantly proceeds via ring-closing metathesis of the monomer and backbiting from the dimer and trimer, but not from higher oligomers as their formation is suppressed. This leads to the observed high MMC selectivity, reaching 60 % at a 25 mM substrate concentration.

Olefin Metathesis in Confinement: Towards Covalent Organic Framework Scaffolds for Increased Macrocyclization Selectivity

“…[15] Smaller substrates can diffuse more easily and penetrate into the COF pores more deeply, where pore confinement effects can take place, favoring RCM for the ring- chain equilibrium products of the reaction by suppressing the formation of higher oligomers. [21,22] . This is likely due to the very large internal surface area of the highly porous COF material that offers enough "inner" pore surface area for this size selective confinement effect to take place and to alter the ring-chain equilibrium.…”

Confinement Effects for Efficient Macrocyclization Reactions with Supported Cationic Molybdenum Imido Alkylidene N-Heterocyclic Carbene Complexes

“…Olefin metathesis is a prime example for catalysis that can be run under constrained geometries. ,− Even though the progress in homogeneous olefin metathesis has brought forward catalysts with high selectivity − and productivity, − heterogeneous systems are also steadily evolving. Over the years, ill-defined systems were replaced by well-defined active sites − that also enabled mechanistic investigations. , In macrocyclization reactions, challenges such as competing oligomerization remain, − particularly in the synthesis of pharmaceutically relevant macrocycles. , Thus, for entropic reasons, the competing acyclic diene metathesis (ADMET) oligomerization can usually only be overcome at very low substrate concentrations of <5 mM and by the use of high catalyst loadings of >1 mol %. ,, It is also known that olefin metathesis-based macrocyclization proceeds to a significant extent via ADMET oligomerization followed by back-biting RCM to form the desired macrocyclic product , (Scheme a).…”

Olefin Metathesis in Confinement: Towards Covalent Organic Framework Scaffolds for Increased Macrocyclization Selectivity

“…In the case of larger substrates, the reaction is mostly catalyzed by catalyst bound on the outer surface and close to the pore openings, mimicking the homogeneous ring‐chain equilibrium [15] . Smaller substrates can diffuse more easily and penetrate into the COF pores more deeply, where pore confinement effects can take place, favoring RCM for the ring‐chain equilibrium products of the reaction by suppressing the formation of higher oligomers [22,23] . This is likely due to the very large internal surface area of the highly porous COF material that offers enough “inner” pore surface area for this size selective confinement effect to take place and to alter the ring‐chain equilibrium.…”