Jawaharlal Nehru Technological University Hyderabad B. Pharmacy II Year PHARMACEUTICAL ORGANIC CHEMISTRY-II Previous Question Paper (August/September - 2022 - R17)

The halogenation of benzene is an electrophilic aromatic substitution reaction. It involves three main steps: generation of the electrophile, formation of the sigma complex, and loss of a proton to restore aromaticity. First, the halogen (X2) reacts with a Lewis acid catalyst (such as FeX3) to form a polarized complex or a free electrophilic ion (X+). Second, the electrophile attacks the benzene ring to form a resonance-stabilized carbocation intermediate known as the sigma complex or arenium ion. Finally, the catalyst removes a proton from the sp3-hybridized carbon, restoring the aromatic system.

Halogens are deactivating because they are highly electronegative, which withdraws electron density from the benzene ring through the inductive effect, making the ring less reactive toward electrophiles. However, they are ortho/para directing due to the resonance effect. The lone pairs on the halogen atom can be delocalized into the ring, which stabilizes the ortho and para carbocation intermediates through the formation of an additional resonance structure where the halogen shares a double bond with the ring. This resonance stabilization lowers the activation energy for ortho and para substitution compared to meta substitution.

Friedel-Crafts acylation involves the substitution of an acyl group (RCO-) onto the benzene ring using an acyl halide (RCOX) and a Lewis acid catalyst (AlCl3). The mechanism proceeds as follows:

1. Formation of the acylium ion: The Lewis acid reacts with the acyl halide to form a stable acylium ion (R-C≡O+).
2. Electrophilic attack: The acylium ion acts as a strong electrophile and attacks the benzene ring to form a resonance-stabilized sigma complex.
3. Deprotonation: The AlCl4- ion abstracts a proton from the sigma complex, regenerating the aromatic ring and the catalyst, and releasing HCl as a byproduct.