Challenging Metathesis Catalysts with Nucleophiles and Brønsted Base: Examining the Stability of State-of-the-Art Ruthenium Carbene Catalysts to Attack by Amines

[Image: see text] Critical to advancing the uptake of olefin metathesis in leading contexts, including pharmaceutical manufacturing, is identification of highly active catalysts that resist decomposition. Amines constitute an aggressive challenge to ruthenium metathesis catalysts. Examined here is the impact of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), morpholine, n-butylamine, and triethylamine on Ru metathesis catalysts that represent the current state of the art, including cyclic alkyl amino carbene (CAAC) and N-heterocyclic carbene (NHC) complexes. Accordingly, the amine-tolerance of the nitro-Grela catalyst RuCl(2)(H(2)IMes)(=CHAr) (nG; Ar = C(6)H(4)-2-O(i)Pr-5-NO(2)) is compared with that of its CAAC analogues nGC1 and nGC2, and the Hoveyda-class catalyst RuCl(2)(C2)(=CHAr′) HC2 (Ar′ = C(6)H(4)-2-O(i)Pr). In C1, the carbene carbon is flanked by an N-2,6-Et(2)C(6)H(3) group and a CMePh quaternary carbon; in C2, by an N-2-(i)Pr-6-MeC(6)H(3) group and a CMe(2) quaternary carbon. The impact of 1 equiv amine per Ru on turnover numbers (TONs) in ring-closing metathesis of diethyl diallylmalonate was assessed at 9 ppm Ru, at RT and 70 °C. The deleterious impact of amines followed the trend NEt(3) ∼ NH(2)(n)Bu ≪ DBU ∼ morpholine. Morpholine is shown to decompose nGC1 by nucleophilic abstraction of the methylidene ligand; DBU, by proton abstraction from the metallacyclobutane. Decomposition was minimized at 70 °C, at which nGC1 enabled TONs of ca. 60 000 even in the presence of morpholine or DBU, vs ca. 80 000 in the absence of base. Unexpectedly, H(2)IMes catalyst nG delivered 70–90% of the performance of nGC1 at high temperatures, and underwent decomposition by Brønsted base at a similar rate. Density functional theory (DFT) analysis shows that this similarity is due to comparable net electron donation by the H(2)IMes and C1 ligands. Catalysts bearing the smaller C2 ligand were comparatively insensitive to amines, owing to rapid, preferential bimolecular decomposition.