Let's break down the synthesis problem step by step: --- ## **Goal** **Synthesize:** The target molecule is a precursor proparacaine, and its is: - A para-substituted phenol core (from p-cresol) - Para position: \(-CH_2NHC(O)CH_2CH_2CH_3\) (A propionamide group attached via a methylene linker to the aromatic ring) ## **Allowed Starting Materials** - **p-cresol** (4-methylphenol) - **Any inorganic reagent** - **Any alcohol with 3 or fewer carbons** --- ## **Step 1: Structure Analysis** ### **p-Cresol:** Benzene ring, para to OH is a methyl group. ### **Target:** Benzene ring, para to OH is a chain: \[-CH_2NHC(O)CH_2CH_2CH_3\] This is N-propionylmethylamine para to a phenol. --- ## **Step 2: Retrosynthetic Analysis** ### **Disconnections:** 1. **Amide formation:** \[-NHC(O)CH_2CH_2CH_3\] can be formed by reacting an amine group (\(-NH_2\)) with propanoyl chloride (or propanoic acid + activating agent). 2. **Benzylamine connection:** The \(-CH_2NH_2\) group can be installed via nucleophilic substitution (like via a benzyl halide intermediate from p-cresol). --- ## **Step 3: Forward Synthesis** ### **(A) Convert p-cresol to p-hydroxybenzyl bromide** 1. **Side Chain Bromination:** - **React p-cresol with Br\(_2\) and light** to brominate the methyl group to benzyl bromide: - p-cresol (4-methylphenol) → p-hydroxybenzyl bromide \[ \ce{C6H4(OH)-CH3 + Br2 (hv) -> C6H4(OH)-CH2Br} \] ### **(B) Nucleophilic Substitution to Amino Group** 2. **Substitution with Ammonia:** - **React p-hydroxybenzyl bromide with NH\(_3\):** - p-hydroxybenzyl bromide → p-hydroxybenzylamine \[ \ce{C6H4(OH)-CH2Br + NH3 -> C6H4(OH)-CH2NH2} \] ### **(C) Prepare Propionyl Chloride** 3. **From Ethanol (2-carbon alcohol) + Inorganic Reagents:** - **Oxidize ethanol to acetic acid, then homologate to propanoic acid, then convert to propionyl chloride.** - **Alternatively, use 1-propanol (3-carbon alcohol):** - Oxidize 1-propanol to propanoic acid (using Jones oxidation: CrO\(_3\)/H\(_2\)SO\(_4\)), then react with SOCl\(_2\) to get propionyl chloride. \[ \ce{CH3CH2CH2OH + CrO3/H2SO4 -> CH3CH2COOH} \] \[ \ce{CH3CH2COOH + SOCl2 -> CH3CH2COCl} \] ### **(D) Amide Formation** 4. **React p-hydroxybenzylamine with propionyl chloride:** - This gives the target amide. \[ \ce{C6H4(OH)-CH2NH2 + CH3CH2COCl -> C6H4(OH)-CH2NHCOCH2CH2CH3} \] --- ## **Summary of Steps** 1. **Brominate p-cresol** (at benzylic position) to get **p-hydroxybenzyl bromide**. 2. **React with NH\(_3\)** to get **p-hydroxybenzylamine**. 3. **Oxidize 1-propanol** to **propanoic acid**, then **convert to propionyl chloride**. 4. **React propionyl chloride with p-hydroxybenzylamine** to get the **target amide**. --- ## **Final Answer** ### **Stepwise Synthesis:** 1. **p-Cresol → p-hydroxybenzyl bromide** - Br\(_2\), light 2. **p-hydroxybenzyl bromide → p-hydroxybenzylamine** - NH\(_3\), excess 3. **1-propanol → propanoic acid** - CrO\(_3\)/H\(_2\)SO\(_4\) (Jones reagent) **propanoic acid → propionyl chloride** - SOCl\(_2\) 4. **p-hydroxybenzylamine + propionyl chloride → Target compound** - Amide formation (base, e.g., pyridine, to neutralize HCl) --- ## **Overall Reaction Scheme** ```markdown p-cresol | [Br2, hv] ↓ p-hydroxybenzyl bromide | [NH3] ↓ p-hydroxybenzylamine | [CH3CH2CH2OH, CrO3/H2SO4, SOCl2] ↓ propionyl chloride | [p-hydroxybenzylamine + propionyl chloride] ↓ **Target compound** ``` --- ### **Final Product:** \[ \boxed{ \text{4-(propionylamino)methylphenol} } \] That is, **p-hydroxybenzylamine propionylated at the amine**. --- **Let me know if you want detailed mechanisms for any of these steps!**