Reactions

The Hofmann elimination starts with the nucleophilic substitution of iodomethane by the primary amine, yielding an alkylammonium salt. This intermediate is then deprotonated by a base, regenerating a neutral secondary amine. This sequence of nucleophilic substitution followed by deprotonation occurs a second time, producing a tertiary amine. A final alkylation then takes place, leading to a quaternary ammonium iodide salt. At this stage, treatment with silver oxide converts iodide into an insoluble silver iodide precipitate along with a silver alkoxide. This latter is hydrolyzed by water, releasing a hydroxide ion. A concerted E2 elimination then occurs: the hydroxide deprotonates H_A while the quaternary ammonium departs simultaneously as a leaving group (LG), affording the alkene product.

Regioselectivity: According to Zaitsev’s ruel, one might expect deprotonation of H_B, as it would yield the more substituted and thermodynamically more stable alkene. However, the E2 mechanism requires a strict antiperiplanar geometry between the proton being abstracted and the LG. Analysis of the Newman projections reveals that when H_B is placed in an antiperiplanar arrangement relatively to the LG, a significant steric clash arises between the methyl group of N(Me)₃ and R₃, destabilizing this conformation (illustrated by the projection viewed from the black ball). In contrast, the conformation in which H_A is antiperiplanar to the LG (illustrated by the projection viewed from the red ball) presents reduced steric strain. Consequently, H_A is selectively deprotonated, affording the less substituted alkene.


Silver oxide treatment: Iodide acts as a nucelophile toward one of the Lewis-acidic silver centres, whose very low solubility drives the reaction and releases the strongly basic AgO^- anion. This latter deprotonates a water molecule to give silver hydroxide (AgOH) and a hydroxide ion.