Past exam of the chemistry B course of the University of Cambridge / 2025 / Paper 1 / B1 / a

Number the fused heterocycle as a 2,3-dihydrobenzofuran: oxygen is position 1 and the acetamido substituent occupies aromatic position 6. Position 5 is the preferred site of electrophilic substitution. It is para to the ring oxygen and ortho to the acetamido group, so both groups stabilize its Wheland intermediate by resonance donation. Position 7 also receives donation, but lies between the two substituents and is more crowded. Position 4 lacks the same combination of directing effects.

The aryl oxygen donates a lone pair into the aromatic system. The acetamido nitrogen can also donate into the ring, although its lone pair is shared with its own carbonyl group, so it is less activating than a free amino group. Comparing resonance-stabilized intermediates and steric accessibility gives the position-5 prediction; simply counting heteroatoms does not.

The product is N-[5-(2-chloroacetyl)-2,3-dihydrobenzofuran-6-yl]acetamide, with an aromatic $-\mathrm{COC}{\mathrm{H}}_2\mathrm{Cl}$ substituent at position 5. Substitution of one aromatic hydrogen by ${\mathrm{C}}_2{\mathrm{H}}_2\mathrm{ClO}$ gives the stated molecular formula. This positional assignment also agrees with the isolated intermediate reported in the original process study.^[ref]

GaCl3 activates chloroacetyl chloride by Lewis-acid coordination and chloride abstraction, represented by the acylium/contact-ion-pair limit $\mathrm{ClC}{\mathrm{H}}_2\mathrm{C}{\mathrm{O}}^{+}$. The position-5 aromatic $\pi$ bond attacks the acyl carbon, giving a Wheland intermediate. Removal of the proton at that carbon restores aromaticity. Product–Lewis-acid coordination is reversed on work-up. The carbon-bound chlorine survives; the chlorine on the acyl carbon is the leaving group.