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Synthesis

Benzene yields to nucleophilic substitution

A calcium hydride reagent mediates the improbable attack of an alkyl nucleophile on an electron-rich aromatic ring

by Stephen K. Ritter
December 4, 2017 | APPEARED IN VOLUME 95, ISSUE 48

With the aid of a powerful calcium reagent, researchers have achieved a bit of molecular trickery to do what many synthetic organic chemists thought wasn’t possible: They have carried out the first nucleophilic alkylation of benzene (Science 2017, DOI: 10.1126/science.aao5923). Friedel-Crafts alkylation is a classic example of electrophilic aromatic substitution. A Lewis acid such as AlCl3 binds the halogen of an alkyl halide, creating a positive charge on the alkyl group. This electron-poor species—an electrophile—is attracted to an electron-rich substrate—a nucleophile—such as benzene’s aromatic ring. The alkyl group then displaces a benzene hydrogen, producing an alkylbenzene. An electron-rich nucleophilic species would normally be repelled by benzene, unless an electron-withdrawing group already on the ring activates it toward nucleophilic attack. Nevertheless, a team led by Michael S. Hill of the University of Bath and Laurent Maron of the University of Toulouse found a way to allow nucleophiles to react with unsubstituted benzene in spite of the electronic repulsion. The researchers developed a calcium hydride reagent that reacts with alkenes to create an alkylcalcium species, which has nucleophilic alkyl groups by virtue of polarized calcium-carbon bonding. They show that the calcium reagent can readily alkylate benzene.

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