Iron-Catalyzed Coupling of Aryl Grignard Reagents with Alkyl Halides: A Competitive Hammett Study**

The use of transition-metal catalysis to form new C C bonds is an important tool in organic synthesis. Palladiumand nickel-catalyzed C C bond-forming reactions have been extensively explored and are well understood. The use of iron as the catalyst has gained much less attention, despite the innovative work of Kochi et al. in the 1970s. Recently, several groups have turned their attention towards iron-catalyzed coupling reactions; this growing interest in iron is due to its environmentally benign character, low cost, and non-toxicity. Furthermore, iron seems to allow all possible combinations of carbon hybridization in the coupling reaction. We have recently published a mechanistic investigation into the iron-catalyzed coupling reaction between an aryl electrophile and an alkyl Grignard reagent. A combination of reaction monitoring, a Hammett competition study, and DFT calculations indicated that the oxidation state of the catalytically active iron species is Fe and that the oxidative addition of the aryl halide is the rate-limiting step. The most important factor for achieving high conversion was slow addition of the Grignard reagent; fast addition caused precipitation of iron, presumably due to over-reduction. Herein, we investigate the electronic effects on the nucleophile by use of a competitive Hammett study (Scheme 1). With the more weakly reducing aryl Grignards, it was found that the catalyst is stable in diethyl ether without additives. Cyclohexyl bromide was added in aliquots to a mixture of p-substituted and unsubstituted phenyl magnesium bromide and consumed after each addition without adverse effects on the catalytic efficiency. Product formation was followed by GC, with samples taken before each addition of the electrophile. In the previous study employing strongly reducing alkyl Grignard reagents, catalyst deactivation could be visibly detected as a darkening of the solution, followed by precipitation. In this study, no deactivation was observed, despite the large excess of aryl Grignard present and the absence of stabilizing additives, demonstrating the lower reducing power of aryl Grignard reagents. In analyzing the competition reaction data, we assumed that the kinetic dependence on all reagents and catalysts is the same for both substrates (X and H, for p-substituted and unsubstituted phenyl magnesium bromides) and that the reaction is first order in Grignard reagent. The relative rate (krel=kX/kH) is then obtained as the slope of a plot of ln([X]0/[X]) against ln([H]0/[H]), that is, the initial and instantaneous concentrations of each Grignard reagent. Since these cannot be measured directly, they were calculated by comparing the instantaneous to the final product concentrations after addition of excess cyclohexyl bromide. Note that the analysis is insensitive to absolute concentration; only relative concentrations need to be well described. All plots gave straight lines with correlation coefficients r>0.99 (Figure 1), indicating both that the assumptions we made were valid and that no significant side reactions occurred. Inspection of the trends indicates that some curvature can be detected in, for example, the case of the CF3-substituted Grignard, introducing a minor uncertainty in krel for this substituent, but it is clear from the plot that the possible deviation between the slopes in the initial and final phases of the reaction are too small to affect the conclusions drawn in this study. An alternative method of estimating the relative concentration of the Grignard reagent would be to analyze the amount of protonation product (benzene and substituted benzene) after workup. The protonation products are also [a] A. Hedstrçm, Prof. P.-O. Norrby Department of Chemistry, University of Gothenburg Kemig rden 4, 412-96, Gothenburg (Sweden) Fax: (+46)31-772-38-40 E-mail : [email protected] [b] U. Bollmann, J. Bravidor Institute of Inorganic and Analytical Chemistry Friedrich Schiller University Jena Lessingstrasse 8, 07743, Jena (Germany) [**] NMP (N-methyl-2-pyrrolidone), the most commonly employed additive combined with alkyl Grignard reagents, inhibits product formation in this reaction. Scheme 1. Competitive coupling of aryl Grignard reagents; I.S.= internal standard.