Question

Consider the synthesis of ibuprofen, a common pain reliever. Starting with benzene and propene, propose a detailed retrosynthesis of ibuprofen. Include all necessary reagents and reaction steps, as well as any potential issues with the synthesis pathway.

Answer 1

To synthesize ibuprofen from benzene and propene, we can follow these retrosynthetic steps:1. Start with the ibuprofen structure: 2- 4-isobutylphenyl propanoic acid.2. Disconnect the carboxylic acid group to obtain the corresponding alcohol: 2- 4-isobutylphenyl propan-1-ol.3. Disconnect the isobutyl group to obtain the corresponding phenol: 4-isobutylphenol.4. Disconnect the isobutyl group to obtain the benzene ring: phenol.Now, we can outline the forward synthesis steps:Step 1: Friedel-Crafts Alkylation of Benzene with PropeneReagents: Propene, AlCl3  catalyst Product: Isopropylbenzene  cumene Step 2: Cumene Hydroperoxide FormationReagents: O2, N2H4  hydrazine , H2OProduct: Cumene hydroperoxideStep 3: Cumene Hydroperoxide RearrangementReagents: H2SO4  catalyst Product: Phenol and acetoneStep 4: Friedel-Crafts Alkylation of Phenol with PropeneReagents: Propene, AlCl3  catalyst Product: 4-isobutylphenolStep 5: Grignard ReactionReagents: Mg, diethyl ether, dry ice  CO2 Product: 2- 4-isobutylphenyl propan-1-olStep 6: Oxidation of Alcohol to Carboxylic AcidReagents: Jones reagent  CrO3, H2SO4, H2O Product: 2- 4-isobutylphenyl propanoic acid  ibuprofen Potential issues with the synthesis pathway:1. Friedel-Crafts alkylation is prone to multiple alkylations and may lead to polyalkylated products. Using a large excess of benzene can help minimize this issue.2. Friedel-Crafts alkylation of phenol can lead to ortho- and para-substituted products. However, the para-substituted product  4-isobutylphenol  is the major product due to steric hindrance at the ortho position.3. The Grignard reaction requires anhydrous conditions, as the presence of water will react with the Grignard reagent and deactivate it. Careful drying of solvents and glassware is necessary.4. The oxidation of alcohol to carboxylic acid using Jones reagent can lead to over-oxidation of the product. Careful control of reaction conditions and monitoring the reaction progress can help minimize this issue. Alternative oxidation methods, such as PCC  pyridinium chlorochromate  or DMP  Dess-Martin periodinane , can also be considered for a more controlled oxidation.