En route: optimisation of reaction conditions and co-catalyst employment to favour Grubbs second generation catalyst mediated cross-metathesis

Abstract

The use of additives in olefin cross-metathesis reactions which employs the commercially available Grubbs’ second generation catalyst, GII, has resulted in better catalyst performance, catalyst stability, suppression of other non-metathetic reactions like olefin isomerization, self- metathesis and improved desired metathesis product yield. The addition of p-cresol to GII enhances selectivity for cross-metathesis over self-metathesis, with 100 equivalents of p-cresol ensuring optimal catalyst performance. Optimisation of the metathesis reaction conditions were performed between trans-1-methoxy-4-(1-propenyl)benzene and 2-ethylhexyl acrylate, varying trans-1-methoxy-4-(1-propenyl)benzene mole fractions from approximately 0.09 to 0.91 suggesting that the CM pathway is kinetically more favourable. The 31P NMR study between GII and p-cresol showed that the cresol binds to the tricyclohexylphosphine oxide preventing the oxide from decomposing the active catalyst. The reaction progress was monitored using 1H NMR spectroscopy at 25 °C and 35 °C in CD2Cl2 solvent over 722 minutes, maintaining a constant p-cresol/GII ratio (100:1, X1 = 0.33). The reaction setup followed previous protocols with slight adjustments for time-trace analysis. Results revealed an induction period at both temperatures, significantly shorter at 35 °C (4 minutes vs. 40 minutes at 25 °C). The elevated temperature notably favours the selectivity of the p-cresol/GII catalyst. Reaction kinetics showed the cross-metathesis rate with the modified catalyst was approximately 1.5 times faster than self-metathesis, with k'obs values of 0.0575 min-1 (25 °C) and 0.68 min-1 (35 °C) for cross-metathesis compared to 0.033 min-1 and 0.41 min-1 for self-metathesis, respectively. Further optimisation was carried using different solvents in the metathesis reaction between trans-1-methoxy-4-(1-propenyl)benzene and 2-ethylhexyl acrylate. The UV-Vis kinetics revealed that the phosphine (PCy3) ligand dissociation equilibrium from Grubbs second generation catalyst (GII) in different solvents (dichloromethane, dichloroethane, chloroform, tetrahydrofuran, and toluene) were determined to be pseudo first order with k'obs = 4.8 - 15.6 x 10-3 min-1. According to an electrochemical study using Cyclic Voltammetry (CV) in the different solvents, an electrochemically reversible behaviour was observed for GII dissolved in the chlorinated solvents (DCM, DCE, and CLF). The formal reduction potentials, E°', of GII in the different chlorinated solvents increased as the polarity index of the solvent became larger. In THF, however, only the oxidation of GII could be detected. Upon oxidation of GII, THF (with a lone pair electron on the oxygen) which is highly coordinative solvent, nucleophilically attach to the electrochemically produced Ru●+, resulting in a redox inactive THF associated compound. A correlation was established between the ease of GII oxidation in the different solvents and the rate of PCy3 dissociation in that solvent. The % yield of the cross-metathesis product in the different solvents at 40 °C catalysed by GII exponentially increased as the Gutmann donor number of the solvent increased, with DCM showing highest yield. In THF, no metathesis could be detected, agreeing the electrochemical data, that THF coordinate to the positively charged or active GII rending it inactive. Non-structural modification of Grubbs’ second generation catalyst involving the use of additives such as phenol derivatives (4-nitrophenol (NP), 4-(trifluoromethyl)phenol (TFP), 4-bromophenol (BP), phenol (P), 4-methoxyphenol (MOP), 4-tertbutylphenol (TBP), 3-methylphenol (3MP, m- cresol), 4-methylphenol (4MP, p-cresol), 2-methylphenol (2MP, o-cresol) and 4-propylphenol (PP) are investigated. The catalyst behaviour and interactions between GII and the different phenol derivatives were characterised using UV-Vis spectroscopy, attenuated total reflection Fourier transformed infrared (ATR-FTIR), and CV. The ATR-FTIR spectra revealed distinct C-N and C-P stretching frequencies from the GII-phenol adducts, alongside phenol-associated O-H and C=C stretching bands. UV-Vis spectra displayed strong absorption bands at 335 nm and weaker bands between 503-509 nm, linked to metal-ligand charge transfer. CV showed electrochemical reversibility for most GII-phenol adducts, except those with electron-withdrawing groups. Metathesis reactions were performed between trans-1-methoxy-4-(1-propenyl)benzene and 2- ethylhexyl acrylate, revealing a correlation between electron-donating phenol groups and higher cross-metathesis (CM) yield. While phenol derivatives influenced catalyst activation rates, no direct correlation was found between activation rates and catalytic selectivity. The study highlights the significance of electron-donating phenol derivatives in enhancing catalytic efficiency by increasing Ru centre electrophilicity.