Q3(c). Benzyne isotope effect; Stevens ring enlargement

Introduction. (i) is nucleophilic substitution of an unactivated aryl halide by NH₂⁻, which goes by elimination–addition through benzyne; deuterium at the ortho positions tests whether C–H breaking is rate-limiting. (ii) is a quaternary ammonium salt treated with a strong base: an ammonium ylide forms and rearranges.

(i) Products and relative rates

Reaction 1. NH₂⁻ removes the ortho H; bromide leaves to form benzyne; NH₂⁻ adds to either end and NH₃ protonates the aryl anion. Product: aniline.

Reaction 2. Here both ortho positions carry D, so NH₂⁻ must remove D⁺. The benzyne formed keeps one D, next to the triple bond. Addition at the former C–Br carbon gives aniline-2-d; addition at the other end gives aniline-3-d, in roughly equal amounts. (The proton that ends on the ring comes from NH₃.)

Scheme: Elimination–addition: the NH₂ enters at C-1 or at C-2 of the benzyne.

Which is faster? Reaction 1. The slow step is removal of the ortho hydrogen (together with, or just before, loss of Br⁻). A C–D bond has a lower zero-point energy than C–H, so it needs more energy to break: a primary kinetic isotope effect, k_H/k_D≈ 5 (Roberts' value for bromobenzene-2-d is 5.5). A large k_H/k_D is itself evidence that benzyne formation, not addition of NH₂⁻, is rate-determining.

(ii) X and Y: Stevens ring enlargement

X. Methyl iodide quaternises the tertiary amine: X = 2-benzyl-2-methyl-1,2,3,4,5,6-hexahydro-2-benzazocinium iodide.

Y (mechanism).

1. NH₂⁻ removes the most acidic proton, a benzylic H of the exocyclic N-CH₂Ph, giving the ammonium ylide N+-CH⁻Ph.
2. The ring CH₂ that links N to the benzo ring (also benzylic, a good migrating group) moves from nitrogen to the carbanion carbon: a [1,2]-Stevens rearrangement. It goes by homolysis of this N–C bond to a radical pair inside the solvent cage and fast recombination, so the migrating carbon keeps its configuration.
3. The ylide carbon is inserted into the ring: the eight-membered ring grows to nine atoms, and nitrogen becomes a tertiary amine again.

Scheme: Y = 3-methyl-2-phenyl-2,3,4,5,6,7-hexahydro-1H-3-benzazonine (one-carbon ring enlargement)

A Sommelet–Hauser [2,3] shift would need an ylide carbon that can reach the ortho carbon of a benzyl group; with this ring the Stevens [1,2] product is formed as the sole product.

Conclusion. (i) Reaction 1 gives aniline; Reaction 2 gives aniline-2-d and aniline-3-d. Reaction 1 is faster (primary isotope effect, about 5), because breaking the ortho C–H bond to form benzyne is rate-determining. (ii) X = the N-benzyl-N-methyl ammonium salt; Y = the ring-enlarged 3-methyl-2-phenyl-3-benzazonine, by a Stevens [1,2] shift of the ammonium ylide.

Application. Benzyne routes are used to make substituted anilines and natural-product skeletons; ammonium-ylide ring enlargements give medium-ring amines found in alkaloids and in some CNS drugs.