What is the initiation step of the Grubbs-Hoveyda olefin metathesis catalyst?w

The ground-breaking advances in catalytic olefin metathesis by Grubbs and others have revolutionized many aspects of organic synthesis, ensuring a high general level of interest in the key metal alkylidene catalysts. The mechanism of ruthenium-mediated olefin metathesis catalysed by first (1a) and second generation (1b) Grubbs complexes has been extensively studied both by experiment and by computational modelling. The rate constants for the initiation of the phosphane-containing catalysts are independent of the olefin concentration. The corresponding activation parameters for phosphane exchange have been measured and it is accepted that the initial dissociation of the phosphane ligand is the highest barrier on the potential energy surface. An important class of pre-catalyst in which both the phenyl group and the PCy3 ligand are replaced by an iso-propoxystyrene (e.g. 1c), and which displays excellent thermal stability and oxygenand moisture-tolerance was synthesised by Hoveyda et al. There is much current interest in the initiation mechanism, because it is central to a detailed understanding of the catalytic activity. Indeed, the timing of the events around the metal centre is critical for a fundamental understanding of the interplay of structure and reactivity in alkene metathesis chemistry. Plenio and co-workers have studied the kinetics of the initiation step using ethyl vinyl ether (EVE) as the substrate, which leads to catalytically inactive Fischer-type carbenes following a single olefin metathesis event, and with diethyl diallylmalonate (DEDAM) which leads to a ring-closing metathesis (RCM) reaction. For both substrates the kinetics are complex, with the rate constants depending upon olefin concentration, suggesting that the olefin is involved in the rate determining step. The rates for the initiation reactions differ by only a factor of 4 (though highly electron deficient haloalkenes are less reactive by a factor of up to 10), so that the reaction energetics are relatively insensitive to the structure of the substrate. The initiation mechanism of the Grubbs-Hoveyda precatalysts is less well understood than those of Grubbs’ first and second generation pre-catalysts. Three possible initiation mechanisms for the Grubbs-Hoveyda pre-catalyst termed dissociative, associative and interchange have been discussed in the literature. The simplest initiation mechanism (dissociative) involves rupture of the Ru–O(alkoxy) bond to create a vacant Ru binding site for the incoming olefin substrate. This behaviour resembles the mechanism favoured for the first and second generation Grubbs complexes, which is supported by evidence from computational and solution experimental studies. Alternative mechanisms involve the olefin itself. Thus we can envisage a mechanism in which the olefin forms a six-coordinate intermediate with the Ru complex (associative), or an interchange mechanism involving simultaneous olefin binding and alkoxy dissociation. No computational studies of the alternative initiation mechanisms have been reported, although a barrier in the range 17–25 kcal mol 1 has been calculated for the dissociative step.