Justin A. M. Lummiss

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty-Chemicals Manufacturing.

The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.

Chemical Plants: High-Value Molecules from Essential Oils

As society faces a future of dwindling petrochemical supplies at increasing cost, much attention has been focused on methods to degrade biomass into renewable commodity-chemical building blocks. Reported here is a powerful complementary approach that amplifies the complexity of molecular structures present in plant materials. Essential-oil phenylpropenoids are transformed via acrylate cross-metathesis into potent antioxidants that are widely used in perfumery and cosmetics, and in treating disorders associated with oxidative damage.

Ethylene-Promoted versus Ethylene-Free Enyne Metathesis

The role of ethylene in promoting metathesis of acetylenic enynes is probed within the context of ring-closing enyne metathesis, using first- and second-generation Grubbs catalysts. Under inert atmosphere, rapid catalyst deactivation is observed by calibrated GC-FID analysis for substrates with minimal propargylic bulk. MALDI-TOF mass spectra reveal a Ru(enyne)(2) derivative that exhibits very low reactivity toward both enyne and ethylene. Under ethylene, formation of this species is suppressed. Enynes with bulky propargylic groups are not susceptible to this catalyst deactivation pathway, even under N(2) atmosphere.

Amine‐Mediated Degradation in Olefin Metathesis Reactions that Employ the Second‐Generation Grubbs Catalyst

Amine‐mediated decomposition during olefin metathesis reactions that employ the second‐generation Grubbs catalyst is studied. For most amines, the dominant deactivation pathway involves ejection of the PCy3 (Cy=cyclohexyl) ligand by the amine, followed by abstraction of the methylidene moiety from the resting‐state species RuCl2(H2IMes)(PCy3)(=CH2) (H2IMes=1,3‐dimesityl‐4,5‐dihydroimidazol‐2‐ylidene) as [MePCy3]Cl. An exception is highly basic 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), which is slow to degrade the resting‐state methylidene complex, and for which the phosphonium byproduct is not observed. However, DBU is shown to rapidly attack a species generated during catalysis, most probably the metallacyclobutane intermediate.

Targeting an Achilles heel in olefin metathesis: A strategy for high-yield synthesis of second-generation Grubbs methylidene catalysts

The first clean, high-yield route is presented to methylidenes RuCl2(L)(PCy3)(CH2) (L = H2IMes or IMes), key vectors for catalysis and deactivation in many olefin metathesis reactions. (H2IMes = N,N′-bis(mesityl)imidazolin-2-ylidene; IMes = N,N′-bis(mesityl)imidazol-2-ylidene).

Clean, Convenient, High‐yield Access to Second‐generation Ru Metathesis Catalysts from Commercially Available Precursors

Expedient routes are described to the three dominant ruthenium catalysts currently used for olefin metathesis: the second‐generation Grubbs, Hoveyda, and indenylidene catalysts. Ligand exchange of the first‐generation PCy3 complexes with isolated free H2IMes, followed by treatment with a cation‐ exchange resin to remove the liberated phosphine, affords the clean targets in ≥95 % isolated yield from commercially available precursors, with no workup other than filtration and evaporation.

Isotopic probes for ruthenium-catalyzed olefin metathesis

Routes are described to previously unreported first- and second-generation Grubbs metathesis catalysts bearing a 13C label at the key benzylidene or methylidene site. Improved syntheses of the 2H-labelled isotopologues are also presented. Labelling at the alkylidene position is important because it provides unique, direct information about changes at the active site of the catalyst, and the fate of the [Ru]CHR ligand during catalyst deactivation. A case study demonstrates the power of 13C-labelling in tracking the methylidene moiety in amine-induced decomposition of the second-generation complex RuCl2(PCy3)(H2IMes)(13CH2). Also reported is the solubility of ethylene in C6D6 and CD2Cl2, measured at 296 ± 1.5 K and 101.0 ± 0.8 kPa.

Decomposition of Olefin Metathesis Catalysts by Brønsted Base: Metallacyclobutane Deprotonation as a Primary Deactivating Event

Brønsted bases of widely varying strength are shown to decompose the metathesis-active Ru intermediates formed by the second-generation Hoveyda and Grubbs catalysts. Major products, in addition to propenes, are base·HCl and olefin-bound, cyclometalated dimers [RuCl(κ2-H2IMes-H)(H2C═CHR)]2 Ru-3. These are generated in ca. 90% yield on metathesis of methyl acrylate, styrene, or ethylene in the presence of either DBU, or enolates formed by nucleophilic attack of PCy3 on methyl acrylate. They also form, in lower proportions, on metathesis in the presence of the weaker base NEt3. Labeling studies reveal that the initial site of catalyst deprotonation is not the H2IMes ligand, as the cyclometalated structure of Ru-3 might suggest, but the metallacyclobutane (MCB) ring. Computational analysis supports the unexpected acidity of the MCB protons, even for the unsubstituted ring, and by implication, its overlooked role in decomposition of Ru metathesis catalysts.