Carbonyl To Acetals And Thioacetals

Carbonyl → Acetals/Thioacetals (ROH, RSH, Diols, Dithiols)

Carbonyl + Alcohol/Thiol → (Thio)Acetals — Including Cyclic Protecting Groups

Aldehydes and ketones react reversibly with alcohols (ROH) under Brønsted acid catalysis to give acetals/ketals (two OR groups on the former carbonyl carbon) and with thiols (RSH) under Brønsted or Lewis acid catalysis to give thioacetals/thioketals (two SR groups). Diols (HO–R–OH) and dithiols (HS–R–SH) create five‑ and six‑membered cyclic (thio)acetals used as protecting groups. Water removal (Dean–Stark or sieves) pushes equilibria toward products; aqueous acid hydrolyzes back to the carbonyl. Diols/dithiols are reagents for cyclic protection not products themselves.

Quick Summary

Buttons/modes: (1) Carbonyl + ROH (acetal/ketal), (2) Carbonyl + RSH (thioacetal), (3) Carbonyl + HO–R–OH (cyclic acetal), (4) Carbonyl + HS–R–SH (cyclic thioacetal).
Catalysts: p‑TsOH, H₂SO₄, or BF₃·OEt₂/ZnCl₂ for RSH; keep acidic but not overly oxidizing for thiols.
Driving force: Remove water (Dean–Stark or 3 Å/4 Å sieves); otherwise the equilibrium stops at the hemiacetal/hemithioacetal.
Reversibility: Aqueous acid hydrolyzes acetals rapidly; thioacetals are more acid resistant and often require Hg²⁺/I₂ or Raney Ni (Mozingo) to undo.
Protecting-group logic: Cyclic (thio)acetals from diols/dithiols are robust protecting groups against base/nucleophiles; thioacetals can also be reduced to methylene (umpolung toolkit).

Representation note: bromide is shown when labeling the Lewis-acid/BF₃·OEt₂ activation overlay solely for illustration; any halide or sulfonate that accompanies the catalyst behaves analogously.

Mechanism — Acid/Lewis-Acid Catalyzed Path (8 Steps)

Every mode shares the same polar spine: acid (or BF₃·OEt₂/ZnCl₂) activates the carbonyl, a nucleophile adds to give a (thio)hemiacetal, the hemi-OH is protonated so it can depart, the resulting oxonium collapses, the second heteroatom attacks, and mild workup deprotonates. Diols/dithiols simply perform Steps 3, 5, and 6 intramolecularly.

Step 1 — Protonate the carbonyl oxygen — **Step 1 — Protonate or coordinate the carbonyl oxygen.** H₃O⁺ or BF₃·OEt₂ binds the carbonyl oxygen, polarizing C=O toward attack.

**Step 2 — Nucleophile approaches the activated carbonyl.** ROH/RSH (or one end of a diol/dithiol) attacks the protonated carbonyl, displacing the π bond onto oxygen.

Step 3 — Proton transfer within the (thio)hemiacetal — **Step 3 — Proton shuffle on the hemiacetal.** The newly attached heteroatom transfers a proton to the reagent pool (or to the opposite end of a diol/dithiol), furnishing a neutral (thio)hemiacetal.

Step 4 — Protonate the hemiacetal OH — **Step 4 — Protonate the hemi-OH.** Acid reprotonates the “hemi” hydroxyl so it can depart as water; cyclic variants borrow the second OH/SH to deliver the proton.

**Step 5 — Collapse and loss of water.** The protonated OH leaves as H₂O while the first hetero atom donates into the carbon, giving an oxonium (acetal cation) with a C=O⁺R double bond.

Step 6 — Second ROH/RSH (or other end of the diol/dithiol) attacks — **Step 6 — Second addition.** A new ROH/RSH molecule (acyclic modes) or the tethered OH/SH (cyclic modes) attacks the oxonium as the first hetero reverts to a single bond.

**Step 7 — Water removes the extra proton.** H₂O (or another solvent base) abstracts the proton from the second heteroatom, regenerating H₃O⁺ and revealing the protonated (thio)acetal.

Step 8 — Final deprotonation to give the neutral (thio)acetal — **Step 8 — Final deprotonation.** Loss of the remaining proton furnishes the neutral acetal/ketal or thioacetal/thioketal; continuous removal of H₂O drives the equilibrium toward this product.

Mechanistic Checklist (Exam Focus)

Aldehydes react faster than ketones (lower steric/EWG penalty). Cyclic closures help sluggish ketones by raising effective concentration.
Acid catalysis is mandatory; base rarely works because dehydration is disfavored.
Acetals/ketals are acid-labile/base-stable protecting groups; thioacetals are even more robust (plan hydrolysis or Raney-Ni desulfurization).
Five- and six-member cyclic (thio)acetals are preferred; others are entropically disfavored.
Water removal is required to go past the hemiacetal.
The entire path is closed-shell; do not draw rearranging carbocations.

Worked Examples

Benzaldehyde + MeOH (p‑TsOH, Dean–Stark) → benzaldehyde dimethyl acetal.

ROH button — Benzaldehyde + MeOH (p‑TsOH, Dean–Stark) → benzaldehyde dimethyl acetal.

Cyclohexanone + ethylene glycol (p‑TsOH, toluene, Dean–Stark) → 1,3-dioxolane cyclic ketal.

HO–R–OH button — Cyclohexanone + ethylene glycol (p‑TsOH, toluene, Dean–Stark) → 1,3-dioxolane cyclic ketal.

RSH button — Benzaldehyde + MeSH (BF₃·OEt₂, sieves) → benzaldehyde dimethyl thioacetal (acid‑resistant protection or Mozingo precursor).

HS–R–SH button — Cyclohexanone + 1,3-propanedithiol (BF₃·OEt₂) → 1,3-dithiane cyclic thioacetal (umpolung/Mozingo handle).

Scope & Limitations

Best substrates: Aldehydes; unhindered ketones; cyclic closures with 5/6-member diols/dithiols.
Slower: Sterically hindered ketones or carbonyls bearing strong EWGs; use Lewis acids or heat.
Regiochemistry: Unsymmetrical ketones + diols may give regioisomeric cyclic acetals; choose the diol length accordingly.
Hydrolysis: Acetals hydrolyze in aqueous acid. Thioacetals survive acid/base but need metal salts (Hg²⁺, I₂) or Raney Ni (Mozingo) to revert or reduce to CH₂.
Functional-group tolerance: Avoid strongly oxidizing conditions when thiols are present; protect other acid-sensitive groups before acetalization.

Practical Tips & Pitfalls

Dry solvents, Dean–Stark, or sieves are essential—no water removal means no acetal.
Match catalyst to nucleophile: ROH → mild Brønsted acids (p‑TsOH, H₂SO₄); RSH/HS–R–SH often respond better to BF₃·OEt₂ or ZnCl₂.
For protecting groups, cyclic acetals (ethylene glycol) are more robust than acyclic; cyclic thioacetals withstand even harsher conditions.
Control odor and oxidation when using thiols (work under N₂/Ar, quench waste with bleach).
Plan the endgame: acetals unmask via aq. acid, whereas thioacetals can be leveraged for Mozingo (Raney Ni → CH₂).

Exam-Style Summary

Carbonyl + ROH (acid, −H₂O) → acetal/ketal. Carbonyl + RSH (acid/BF₃·OEt₂, −H₂O) → thioacetal. Diols/dithiols deliver cyclic protecting groups (5/6-member). The mechanism is reversible: protonate carbonyl → (thio)hemiacetal → activate OH → lose H₂O → capture → deprotonate. Remove water to drive forward; add water/acid to unmask. Thioacetals are more acid-resistant and can be desulfurized (Mozingo) to CH₂.

Interactive Toolbox

Mechanism Solver — choose the ROH, RSH, HO–R–OH, or HS–R–SH buttons to watch the 4-mode spine (activate → hemi → oxonium → capture).
Reaction Solver — compare aldehydes vs ketones and diol/dithiol options to predict acyclic vs cyclic products.
IUPAC Namer — generate names for cyclic protecting groups such as 1,3-dioxolanes and 1,3-dithianes.

FAQ

Do acetals form under basic conditions? No. The dehydration step requires acid; base typically stalls at the hemiacetal.

Why use a diol/dithiol instead of two equivalents of ROH/RSH? Diols/dithiols create intramolecular attacks that favor five- or six-member rings, giving robust cyclic protecting groups.

How do I remove a cyclic acetal? Aqueous acid (often dilute HCl, H₂SO₄, or p‑TsOH in MeOH/H₂O) hydrolyzes acetals back to the carbonyl and diol.

How do I unmask a thioacetal? Thioacetals resist simple acid hydrolysis; Hg²⁺/H₂O, I₂/H₂O, or Raney Ni (Mozingo reduction to CH₂) are common strategies.

Why are thioacetals useful beyond protection? They can invert polarity (umpolung) and, upon Raney Ni treatment, reduce a carbonyl to CH₂ in two steps.

Study Tools