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8. Synthesis Strategy & Retrosynthesis

Real synthesis works backwards: pick the target apart into simpler pieces — retrosynthesis — until you reach starting materials you can buy, then run the steps forward. A good route is short, high-yielding, and stereochemically controlled.

Retrosynthetic Analysis

A disconnection (drawn with a ⇒ arrow) breaks a bond into synthons — idealized fragments that correspond to real reagents. Disconnect at bonds that a known reaction can form: C–C bonds from Grignard additions, alkenes from eliminations, alcohols from carbonyl reductions.

Protecting Groups

When a molecule has two reactive sites and you need only one to react, protect the other: acetals protect ketones/aldehydes from nucleophiles and bases, and are removed with aqueous acid.

Worked synthesis: Make 2-butanol from acetylene. Retrosynthesis: 2-butanol ⇒ 2-butene (hydration) ⇒ 2-butyne (Na/NH3 reduction) ⇒ propyne (acetylide alkylation) ⇒ acetylene.
Forward: $\text{HC≡CH} \xrightarrow[\text{2. CH}_3\text{I}]{\text{1. NaNH}_2} \text{CH}_3\text{C≡CH} \xrightarrow[\text{2. CH}_3\text{I}]{\text{1. NaNH}_2} \text{CH}_3\text{C≡CCH}_3 \xrightarrow{\text{Na/NH}_3} \text{trans-2-butene} \xrightarrow{\text{H}_2\text{O/H}_2\text{SO}_4} \text{2-butanol}$
Worked synthesis: Make 2-phenyl-2-propanol from benzene. Friedel–Crafts acylation (CH3COCl/AlCl3) gives acetophenone; methylmagnesium bromide adds to the ketone, and aqueous workup gives the tertiary alcohol.

Practice Problems

  1. Propose a one-step synthesis of ethylbenzene from benzene.
  2. Why would you protect a ketone before using a Grignard reagent elsewhere in the molecule?
  3. Propose a synthesis of tert-butanol from methyl bromide.
  4. What is a synthon?

Answers: 1. Friedel–Crafts alkylation: benzene + CH3CH2Cl / AlCl3   2. The Grignard reagent would attack the unprotected ketone instead   3. CH3Br + Mg → CH3MgBr, then add to acetone, then aqueous workup   4. An idealized fragment in a retrosynthetic disconnection — the piece a real reagent stands in for

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