Protecting Group Strategy: Orthogonality and the Order of Removal · seed 1 · A4, ink-friendly. The answer key prints on its own page for grown-ups.

Scheduling protection across a long route

Science · Chemistry · ages 22-23
Name ______________________   Date ____________

  1. What does orthogonal mean for a pair of protecting groups?

    • Both remove in the same single wash
    • Each removes under conditions leaving the other untouched
    • Neither group can ever be removed

  2. Why do chemists mask carbonyls as acetals?

    • To make them react faster with every reagent
    • To protect them through harsh steps, then unmask with aqueous acid
    • To turn them into better leaving groups for later substitution steps

  3. A capped ether behaves exactly like a free hydroxyl toward strong reagents.

    Circle one:   True   False

  4. A deprotection uses strong base. What must you check first?

    • Which other groups in the molecule would not survive it
    • Whether the solvent is perfectly dry
    • The color of the reaction mixture

  5. Two hydroxyls must free at different points. One mask frees with hydrogen, the other with acid, and each recipe was checked to leave the other mask untouched. Which pair do you pick?

    • Two identical acid labile masks stripped together in one wash
    • Two identical masks stripped by hydrogen
    • One mask stripped by hydrogen and one stripped by acid

  6. A route runs neutral and mild non-aqueous acid steps, with aqueous base plus acidic workup available at the end. When does a methyl ester serve well as the masked acid?

    • When you want a mask that no condition can ever open
    • When every step of the route is strongly acidic and aqueous
    • When the mask stands mild acid steps, then opens with base

  7. A colleague proposes global deprotection to save three steps. The plan sacrifices one ester the target requires, and no restoration step is planned. How do you decide?

    • Always refuse global steps on principle alone without ever counting
    • Refuse: the target needs that ester and no restore is planned
    • Always take the global wash since fewer steps always win

  8. A route strips an acid labile ether while a needed acetal sits nearby. What is the risk?

    • The acetal may also fall, since acid unmasks it too
    • Acetals always survive any acid wash
    • Ethers can never be removed selectively under any conditions
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Answer key

For grown-ups. Fold this page away before handing over the rest.

Scheduling protection across a long route W1-mt_-TvfTGZ-_Z-s1

  1. Each removes under conditions leaving the other untouched · Orthogonal sets free sites in any chosen order.
  2. To protect them through harsh steps, then unmask with aqueous acid · Acetals survive bases and hydrides, then open cleanly at the end.
  3. False · The capped ether sits quiet while the free hydroxyl attacks.
  4. Which other groups in the molecule would not survive it · Stability tables tell you what lives through each strip.
  5. One mask stripped by hydrogen and one stripped by acid · Checked cross stability lets you unveil the sites one at a time.
  6. When the mask stands mild acid steps, then opens with base · A methyl ester stands through the mild steps here; base opens it to carboxylate and acidic workup frees the acid.
  7. Refuse: the target needs that ester and no restore is planned · A target missing a required group is not the target. Refuse unless the loss is acceptable or restored.
  8. The acetal may also fall, since acid unmasks it too · Shared weak spots mean one wash can fell masks you hoped to keep.
Worksheet · LightMySky