Silyl Deprotection Tbaf

Silyl Deprotection of Alcohols (TBAF, F⁻)

Fluoride-based deprotection (most commonly TBAF) converts a silyl ether (RO–SiR₃) back into the free alcohol (ROH). The key driving force is formation of a strong Si–F bond, so the chemistry happens at silicon, not at carbon.

Quick Summary

Reagents/conditions: RO–SiR₃ + TBAF (F⁻) in THF, then aqueous workup.
Outcome: RO–SiR₃ → ROH + R₃SiF.
Mechanism: Two-step substitution at silicon: (1) F⁻ from TBAF attacks Si while Si–O bond breaks simultaneously, giving alkoxide (RO⁻) and silyl fluoride (R₃Si–F); (2) protonation during workup gives ROH.
Stereochemistry: Retained at the alcohol carbon since substitution occurs at silicon, not carbon.
Selectivity: TMS ethers are more labile (removed faster) than TBS ethers. Problems often test selective deprotection.
Common pitfalls: Forgetting that without workup the product is RO⁻ (alkoxide), not ROH. Confusing which silyl group is removed first in molecules with multiple protections.

Mechanism — Two Steps + Product (TBAF Attack/Cleavage, Protonation, Product)

Step 1: TBAF fluoride attacks silicon while Si-O bond breaks. — Step 1 — TBAF attacks silicon: F⁻ attacks Si (shown with full TBAF molecule) while the Si–O bond breaks simultaneously, releasing alkoxide (RO⁻) and silyl fluoride (R₃Si–F). Two curved arrows show the electron flow.

Step 2: Protonation of alkoxide by H3O+. — Step 2 — Protonation: The alkoxide (RO⁻) abstracts a proton from H₃O⁺. Two curved arrows show the proton transfer.

Product: Free alcohol ROH. — Product — The free alcohol (ROH) is formed.

Each frame comes directly from the RDKit builder used in the Mechanism Solver. Substitution occurs at silicon, not carbon. The driving force is formation of the strong Si–F bond (~140 kcal/mol).

Mechanistic Checklist

Substitution occurs at silicon, NOT at carbon — no SN1/SN2 at the alcohol carbon.
No carbocation intermediates — no rearrangements possible.
The driving force is Si–F bond formation (~140 kcal/mol bond energy vs ~90 kcal/mol for Si–O).
Stereochemistry at the alcohol carbon is completely preserved.
Without proton source/workup, the immediate product is RO⁻ (alkoxide), not ROH.

Worked Examples

Ethyl TMS ether + TBAF → Ethanol (fast deprotection)

TBAF reagent button — Ethyl TMS ether + TBAF → Ethanol (fast deprotection)

Cyclohexyl TMS ether + TBAF → Cyclohexanol

Ethyl TBS ether + TBAF → Ethanol (slower than TMS)

Isopropyl TBS ether + TBAF → Isopropanol (2° alcohol example)

tert-Butyl TMS ether + TBAF → tert-Butanol (3° alcohol example)

Ethyl TIPS ether + TBAF → Ethanol (TIPS is more robust than TBS)

Ethyl TBDPS ether + TBAF → Ethanol (TBDPS is most stable)

Each worked example reuses the same SMILES that feed the Mechanism Solver, so what you see here is exactly what appears in the interactive tool.

Scope & Limitations

Feature	TMS Ethers	TBS/TBDMS Ethers	TIPS Ethers	TBDPS Ethers
Fluoride lability	Very fast	Moderate	Slow	Very slow
Selective removal	Removed first	Survives when TMS is present	Survives when TMS/TBS present	Most robust
Typical conditions	TBAF, rt, minutes	TBAF, rt–40°C, hours	TBAF, 40–60°C, hours	TBAF, extended time/heat

Rule of thumb (lability order): TMS > TBS > TIPS > TBDPS. In molecules with multiple silyl protecting groups, TMS is removed first, TBS second, TIPS third, and TBDPS survives the longest under fluoride conditions. This selectivity is frequently tested on exams.

Practical Tips

Selective deprotection: Use controlled TBAF equivalents or short reaction times to remove TMS selectively while leaving TBS intact.
Complete deprotection: Use excess TBAF and longer reaction times to remove all silyl groups.
Alternative fluoride sources: HF·pyridine, TASF, and CsF can also deprotect silyl ethers; HF is more aggressive and can cleave TBS faster.
Moisture sensitivity: TBAF solutions should be fresh; hydrated TBAF may be less effective.
Workup matters: If the problem doesn't show aqueous workup, the product may be RO⁻ rather than ROH.

Exam-Style Summary

Silyl ether + TBAF (F⁻) → alcohol. The mechanism is two steps: (1) F⁻ attacks Si while Si–O breaks simultaneously (driven by strong Si–F bond formation), then (2) protonation gives ROH. Stereochemistry at carbon is retained. TMS is more labile than TBS — expect selective deprotection questions.

Pitfalls to watch for:

Drawing SN2 at the alcohol carbon — substitution occurs at silicon, not carbon.
Forgetting workup — without protonation, the product is RO⁻ (alkoxide), not ROH.
Confusing lability order — TMS is removed faster than TBS.
Missing selective deprotection — if both TMS and TBS are present, TMS comes off first.

FAQ

Why does fluoride remove silyl groups? Silicon has a strong affinity for fluorine (~140 kcal/mol Si–F bond vs ~90 kcal/mol Si–O). This thermodynamic driving force makes fluoride attack at silicon highly favorable.

What's the difference between TMS and TBS under fluoride? TMS ethers are smaller and more accessible, so they're cleaved faster. TBS has a bulky tert-butyl group that slows fluoride attack. In mixed systems, TMS is removed first.

What if the problem doesn't show workup? The immediate product of fluoride deprotection is the alkoxide (RO⁻), not the alcohol (ROH). Protonation happens during aqueous workup. Some problems test this distinction.

Can I deprotect TBS without touching TMS? No — TMS is more labile than TBS. If you treat a molecule with both, TMS is removed first. To selectively remove TBS, you'd need to first remove TMS (or use different conditions).

What about silyl enol ethers? TBAF can also cleave silyl enol ethers and other silyl-protected functionalities. Watch for unintended desilylation in complex molecules.

Interactive Toolbox

Use these tools to explore silyl deprotection:

Mechanism Solver — see the two-step RDKit mechanism for TBAF deprotection on any silyl ether.
Reaction Solver — enter your silyl ether, select TBAF, and confirm the alcohol product.
IUPAC Namer — generate systematic names for your alcohol products.

Study Tools