Organocalcium-mediated nucleophilic alkylation of benzene

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Science  01 Dec 2017:
Vol. 358, Issue 6367, pp. 1168-1171
DOI: 10.1126/science.aao5923

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Calcium can breach benzene's defenses

Calcium plays a major, multifaceted role in biology and mineralogy. In organic chemistry, though, it is largely overlooked and overshadowed by the carbon compounds of its cousins lithium and magnesium. Wilson et al. now report that the element was just biding its time: Several organocalcium compounds that they prepared can alkylate benzene by displacing a hydride, with no need for a more conventionally reactive leaving group such as chloride (see the Perspective by Mulvey). This surprising, previously elusive reaction attests to the unusual nucleophilicity of the carbons bound to calcium.

Science, this issue p. 1168; see also p. 1132


The electrophilic aromatic substitution of a C–H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n-alkyl derivatives—synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride—react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C–D/H bond. These reactions produce the n-alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C–H activation transition state.

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