Organocalcium-mediated nucleophilic alkylation of benzene

Abstract

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 -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 thealkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C-H activation transition state.

Heterolysis of Dihydrogen by Nucleophilic Calcium Alkyls

“…23 The formation of the dimeric compounds 7 – 9 was observed to ensue in a stepwise fashion through the intermediacy of mixed hydride‐alkyl species ( 4 – 6 ). Although 7 – 9 were stable in aliphatic solvents, solutions in benzene at even mildly elevated temperatures (ca.…”

“…Further insight into this proposed mechanism was provided by density functional theory (DFT) calculations carried out with the same computational approach (B3PW91, see SI) previously used to describe the stepwise formation of the dicalcium di‐ n ‐hexyl derivative ( 9 ), through the reaction of compound 3 with 1‐hexene 23. The first 1‐hexene insertion with compound 3 was described in our previous report and the associated barrier yielding the dicalcium n ‐hexyl‐hydride complex C ( 6 ) is 20.1 kcal mol −1 .…”

Coordination of arenes and phosphines by charge separated alkaline earth cations

“…40 These reactions produce the n-alkyl benzenes through the generation of a calcium hydride such that rupture of the C-H bond occurs via an effective S N 2 displacement of H − . Based on the experimental observation that the alkylation displays half order kinetics, it was proposed that the key step in this transformation was the generation of a monomeric and coordinatively unsaturated calcium alkyl.…”

Palladium‐Catalyzed para‐Selective Alkylation of Electron‐Deficient Arenes

“…[1] Fore xample,i n the FDAOrange Book, arenes are the most frequently used skeletons in small-molecule drugs. [2] Friedel-Crafts alkylation occurs by electrophilic aromatic substitution and is usually the reaction of choice owing to the ready availability of alkylating reagents.T his reaction works well with electron-neutral and electron-rich rings such as phenols and anilines,b ut product formation is often accompanied by over-alkylation and isomerizations of primary alkyl groups. [2] Friedel-Crafts alkylation occurs by electrophilic aromatic substitution and is usually the reaction of choice owing to the ready availability of alkylating reagents.T his reaction works well with electron-neutral and electron-rich rings such as phenols and anilines,b ut product formation is often accompanied by over-alkylation and isomerizations of primary alkyl groups.…”