Density function theory calculations reveal that the GrubbsHoveyda olefin metathesis pre-catalyst is activated by the formation of a complex in which the incoming alkene substrate and outgoing alkoxy ligand are both clearly associated with the ruthenium centre. The computed energies for reaction are in good agreement with the experimental values, reported here.

The potential energy surfaces for the activation of Grubbs−Hoveyda-type precatalysts with the substrates ethene, propene, 1-hexene, and ethyl vinyl ether (EVE) have been probed at the density functional theory (DFT) (M06-L) level. The energetically favored pathway of the reaction leading to a 14e Fischer carbene and styrene starts with an initiation step in which the incoming substrate and outgoing alkene ligand are both clearly associated with the ruthenium center. For these substrates, with the exception of ethene, the rate determining step is predicted to be the formation of the metallocyclobutane (MCB). We have taken the initial reactant to be a weak van der Waals complex between substrate and precatalyst. This model yields good agreement between the computed activation parameters for both the parent Grubbs−Hoveyda and Grela complex with EVE substrate, and the experimental values, reported here. The alternative model which takes the initial reactant to be two isolated molecules requires an estimate of the entropy loss on formation of the initial complex in solution which is difficult to evaluate. Our estimate of this quantity yields a barrier for the rate determining step for the interchange mechanism which is close to the value we find for the alternative mechanism in which the rate determining step is the initial dissociation of the precatalyst. The relative energetics of these two mechanisms involving different initiation steps but with similar activation barriers, could well be dependent upon the precatalyst and substrate in line with the recent experimental findings of Plenio and co-workers.

Although Grubbs metathesis catalysts have enabled syntheses of a range of molecules, alkene isomerization, a known and problematic side reaction, is poorly understood. Several mechanisms which have been advanced to account for isomerization were studied by using electronic structure calculations. The pathway catalyzed by a ruthenium hydride emerged as the most facile process by a significant margin. For the first time, we have obtained experimental evidence for the presence of this species in a metathesis‐active system.

Synergic effects between ancillary N-heterocyclic carbenes [(1,3-bis­(2,4,6-trimethylphenyl)-1,3-imidazoline-2-ylidene or 1,3-bis­(2,6-diisopropylphenyl)-1,3-imidazoline-2-ylidene] and chelating benzylidene–ether ligands were investigated by studying initiation rates and kinetic profiles of Hoveyda–Grubbs (HG) type Ru complexes. A newly designed Ru-benzylidene-oxazinone precatalyst 4 was compared with Grela and Blechert complexes bearing modified isopropyloxy chelating leaving groups and with the standard HG complex to understand how the ancillary and the leaving ligands interact and influence the catalytic activity.

No abstract

The reactiono fe nol esters with SelectFluor is facile andl eads to the corresponding a-fluoroketones under mild conditions and, as ar esult, this route is commonly employed for the synthesis of medicinally importantc ompoundss uch as fluorinated steroids. However,d espite the use of this methodology in synthesis, the mechanism of this reactiona nd the influence of structureo nr eactivity are unclear.Arigorous mechanistic study of the fluorination of these substrates is presented,i nformed primarily by detailed and robust kinetic experiments. The resultso ft his study implicateapolar two-electron process via an oxygen-stabilised carbenium species, rather than as ingle-electron process involvingr adical intermediates. The structure-reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of a-fluoroketones.Scheme1.The fluorination of steroid structures via enol ester intermediates.[a] S.Scheme2.Literature studies that implicate two-electron or single-electron reaction mechanisms.Scheme14. Values of 1 for the three different Hammett studies conductedd uring thiswork.Scheme15. Proposed mechanisms for the hydrolysisof( a) 3 and (b) 8c after fluorination.

The 'variable oxygen probe' is applied t o systems with the general structure Y-C-C-OX (Y = F, H, SiR,), using both crystal structure correlations (including 25 n e w structures) and ab initio calculations (SCF[DZP]), for 20 structures, Y-CH,-CH,-OX: Y = H, F and SiH, (gauche and trans); X = CH3, CHO ( E and Z) and NO,. The calculations reproduce conformational preferences well (all our 2-fluoroethyl derivatives crystallise with F gauche to OX). Both crystal and calculated structures give linear bond-length/pK,,, correlations. From the crystal structures: definitive correlations are derived for primary and secondary alcohol derivatives; no significant difference is observed between axial and equatorial cyclohexyl systems; p-fluorine has a small bond-shortening effect on the C-OX bond, which is greatest for the best leaving groups OX; and data for two systems with p-silicon are consistent with a bond-lengthening effect. The inductive effect of p-fluorine, observed as its effect o n the C-OX bond length, shows no significant dependence on geometry. Calculated bond lengths give similar results, but show the different sensitivities to varying OX expected from frontier orbital considerations (G,,-~ -o*c-ox for Y = Si > H > F). The length of the C-OX bond in Y-CH,-CH,-OX is a linear function of the electronegativity of Y. 1,3-lnteraction energies calculated (at the MP2[DZP] level) for the isodesmic reaction Y-CH,-CH,-OX + CH,-CH,+ CH,-CH,-OX + Y-CH,-CH,give a measure of the destablising effect of p-fluorine and the stabilising effect of p-silicon in these systems. In three different systems which react with participation of adjacent o-bonds, the lengthening of the C-OX bond, observed in the ground state using the variable oxygen probe, is not accompanied b y significant involvement of the adjacent orbitals. It is suggested that C-OX bond breaking, and the further structural reorganisation, are not closely coupled in such reactions.Unique mechanistic insight is available from the systematic study of ground-state structures of suitable organic compounds. '.' We have identified a simple relationshipthe longer the bond the faster it breaks-between the length of the bond to oxygen in systems R-OX and the rate at which the same bond is broken in ionic reactions in s ~l u t i o n . ~ R-OX-R+ Paper 1 106 109G

Initiation rates for Grubbs and Grubbs-Hoveyda second generation pre-catalysts have been measured accurately in a range of solvents. Solvatochromic fitting reveals different dependencies on key solvent parameters for the two pre-catalysts, consistent with different mechanisms by which the Grubbs and Grubbs-Hoveyda pre-catalysts initiate.The alkene metathesis reaction is now a standard transformation in academic laboratories, and has been applied to the synthesis of a wide range of natural 1,2 and unnatural products, 3 fine chemicals, 4,5 and polymers. 6 The availability of robust and commercially available pre-catalysts such as 1 and 2 has enabled the rapid growth of alkene metathesis in the synthetic repertoire. Although transition metal catalysts have enabled many efficient large scale processes to be carried out in industry, 5,7 the application of alkene metathesis to industrial processes has been more limited. 7,8For industrial-scale syntheses, the implications of the reaction solvent must be considered carefully; these include costs of purchase, purification, drying, recycling and/or disposal, and the health and safety implications of transport, transfer, storage and use. There are also sustainability issues raised by projected uncertainty of supply and by legislative changes. 9These considerations have led major pharmaceutical companies to encourage their discovery chemists to anticipate scaleup in their laboratory practice and reaction design, 9 replacing solvents which are problematic for scale-up, wherever practicable, and at the earliest stage possible.The classical set of solvents for RCM is dichloromethane (DCM), 1,2-dichloroethane (DCE), benzene and toluene; of these, toluene raises the fewest issues while the other three are problematic. It has been reported that other solvents, including acetic acid, 10 methyl tert-butyl ether (MTBE), 11 dimethyl carbonate 12 and hexafluorobenzene (HFB) 13,14 are particularly effective for RCM, mostly on the basis of reaction yields or qualitative comparisons of kinetic profiles, so the precise locus of any solvent effect is not clear. If solvent effects on reaction chemistry could be revealed in detail, solvents could be selected for scale-up on the basis of both chemical efficacy and sustainability, and from a strong experimental starting point. We therefore sought to reveal the effects of solvent on the initiation rates of 1 and 2, which are currently the most popular metathesis pre-catalysts.Initiation rates were measured for 1 and 2 by reaction of the pre-catalyst with ethyl vinyl ether 15 in a number of solvents.Initiation rates for 1 were obtained following the method of Sanford et al.; 16 the rate-determining step in this reaction is known to be dissociation of the phosphane ligand. The integral versus time data was processed using a simple first order treatment (eqn (1)).For solvents where deuterated analogues were unavailable commercially, 10% v/v chloroform-d was added to enable a deuterium lock.Initiation rates for pre-catalyst 1 cover only a ca. fou...