Question 11 of 13: Synthesis from Benzene (Seven Targets)

Question 11: Synthesis from Benzene (Seven Targets) (20 marks)

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

1. a) 4-Bromoaniline. Nitrate first (nitro is installed via a group, amine, that would over-react/poly-brominate if reactive first), reduce, then brominate the strongly-activated aniline ring (para dominant, sterically preferred over ortho): $$\mathrm{C_6H_6 \xrightarrow{HNO_3,\ H_2SO_4} C_6H_5NO_2 \xrightarrow{Fe,\ HCl} C_6H_5NH_2 \xrightarrow{Br_2\ (1\ eq,\ mild)} \boxed{4\text{-BrC}_6H_4NH_2}}$$
a) 4-bromoaniline — final target
2. b) 1-Bromo-2-methyl-4-nitrobenzene. Install the methyl (o,p-director) first via Friedel–Crafts alkylation, brominate ortho to it (isolate the ortho isomer), then nitrate — both remaining directors (CH₃ ortho/para, Br ortho/para) reinforce the position para to the methyl group: $$\mathrm{C_6H_6 \xrightarrow{CH_3Cl,\ AlCl_3} C_6H_5CH_3 \xrightarrow{Br_2,\ FeBr_3\ (\text{ortho isomer})} 2\text{-BrC}_6H_4CH_3 \xrightarrow{HNO_3,\ H_2SO_4} \boxed{1\text{-Br-2-CH}_3\text{-4-NO}_2\text{-C}_6H_3}}$$
b) 1-bromo-2-methyl-4-nitrobenzene
3. c) NO₂/COCH₃/CH(CH₃)₂ on three consecutive ring carbons. Install the isopropyl group first (Friedel–Crafts alkylation, the only o,p-director available at this stage), acylate ortho to it (the minor Friedel–Crafts regiochemical product — separated from the major para isomer by distillation/chromatography, since the bulky acylium ion prefers para but the ortho isomer is still a real, isolable product), then nitrate: the required nitro position is adjacent to the acetyl group and is isolated as the corresponding minor nitration isomer in the same way (neither remaining director strongly favours this position, but it is a genuine, separable product): $$\mathrm{C_6H_6 \xrightarrow{(CH_3)_2CHCl,\ AlCl_3} C_6H_5CH(CH_3)_2 \xrightarrow[\text{(ortho isomer)}]{CH_3COCl,\ AlCl_3} 2\text{-iPr-C}_6H_4COCH_3 \xrightarrow[\text{(isolate isomer)}]{HNO_3,\ H_2SO_4} \boxed{\text{target}}}$$
c) 1,2,3-trisubstituted target: NO2/acetyl/isopropyl
4. d) 4-Aminobenzoic acid (PABA). Alkylate is not needed — oxidise a methyl group to the carboxylic acid after installing the amine precursor. Nitrate toluene (directed para by the methyl), oxidise the ring methyl to –COOH (hot KMnO₄, which also survives the nitro group), then reduce the nitro to the amine last (KMnO₄ conditions would also oxidise a free amine, so nitro must stay protected as NO₂ until after the oxidation step): $$\mathrm{C_6H_5CH_3 \xrightarrow{HNO_3,\ H_2SO_4} 4\text{-O}_2N\text{-C}_6H_4CH_3 \xrightarrow{KMnO_4,\ \Delta} 4\text{-O}_2N\text{-C}_6H_4COOH \xrightarrow{Fe,\ HCl} \boxed{4\text{-H}_2N\text{-C}_6H_4COOH}}$$
d) 4-aminobenzoic acid (PABA), a sunscreen component
5. e) Sodium 4-propylbenzenesulfonate. Friedel–Crafts alkylation with a primary halide risks carbocation rearrangement, so install the propyl group via acylation + reduction (Clemmensen or Wolff–Kishner) instead, avoiding the 1° cation entirely; then sulfonate (SO₃/H₂SO₄, para-directed by the alkyl group) and neutralise: $$\mathrm{C_6H_6 \xrightarrow{CH_3CH_2COCl,\ AlCl_3} C_6H_5COCH_2CH_3 \xrightarrow{Zn(Hg),\ HCl} C_6H_5CH_2CH_2CH_3 \xrightarrow{SO_3,\ H_2SO_4} 4\text{-Pr-C}_6H_4SO_3H \xrightarrow{NaOH} \boxed{4\text{-Pr-C}_6H_4SO_3^-Na^+}}$$
e) sodium 4-propylbenzenesulfonate
6. f) 3-Bromo-4-propylaniline. The bromine sits meta to the amine (and ortho to the propyl group) — a position no single o,p-director installs directly, so a temporary strong director (nitro→amine) is used to force the halogen to the required carbon, exactly as for target (c): brominate a 4-propyl-nitrobenzene precursor (directed largely by the ring's strongest available activator at that stage) to place Br ortho to the eventual amine, then reduce: $$\mathrm{C_6H_5CH_2CH_2CH_3\ (\text{from e}) \xrightarrow{HNO_3,\ H_2SO_4} 4\text{-Pr-C}_6H_4NO_2 \xrightarrow[\text{(isolate isomer)}]{Br_2,\ FeBr_3} 2\text{-Br-4-Pr-C}_6H_3NO_2 \xrightarrow{Fe,\ HCl} \boxed{3\text{-Br-4-Pr-C}_6H_3NH_2}}$$
f) 3-bromo-4-propylaniline
7. g) 2-Chloro-4-ethylstyrene (vinyl group, Cl ortho to it, ethyl para to the vinyl). A vinyl group cannot be installed directly by electrophilic aromatic substitution (there is no "CH₂=CH⁺" electrophile); it is always built by Friedel–Crafts acylation followed by reduction/dehydration. Install ethyl first (o,p-director), acylate para to it (the major, sterically preferred Friedel–Crafts acylation product — this directly gives the required para relationship between the future vinyl group and the ethyl group), chlorinate ortho to the ketone (isolated isomer, needed to set up the final ortho-Cl/vinyl relationship), then reduce the ketone to the alcohol and dehydrate to install the vinyl group last: $$\mathrm{C_6H_6 \xrightarrow{CH_3CH_2Cl,\ AlCl_3} C_6H_5CH_2CH_3 \xrightarrow[\text{(para)}]{CH_3COCl,\ AlCl_3} 4\text{-Et-C}_6H_4COCH_3}$$ $$\mathrm{\xrightarrow[\text{(isolate isomer, ortho to acetyl)}]{Cl_2,\ FeCl_3} 2\text{-Cl-4-Et-C}_6H_3COCH_3 \xrightarrow{NaBH_4} \text{2-Cl-4-Et-C}_6H_3CH(OH)CH_3 \xrightarrow{H_2SO_4,\ \Delta} \boxed{\text{2-chloro-4-ethylstyrene}}}$$
g) 2-chloro-4-ethylstyrene — final target