Protecting groups: Boc, Fmoc, Cbz, TBS and more
A protecting group blocks a reactive group so that a reaction elsewhere in the molecule works; afterwards it is removed again. Three questions matter: how does it go on, what does it survive, how does it come off?
Amines
Boc (tert-Butyloxycarbonyl)
Protects: amines as a carbamate- Put on with
- Boc₂O, base (Et₃N, NaHCO₃, DMAP)
- Stable to
- bases, nucleophiles, H₂/Pd
- Removed with
- acid: TFA or HCl
Fmoc (Fluorenylmethyloxycarbonyl)
Protects: amines as a carbamate- Put on with
- Fmoc-Cl or Fmoc-OSu, base
- Stable to
- acids (TFA), usually H₂/Pd
- Removed with
- base: piperidine in DMF
Cbz / Z (Benzyloxycarbonyl)
Protects: amines as a carbamate- Put on with
- Cbz-Cl, base
- Stable to
- mild acids and bases
- Removed with
- hydrogenolysis: H₂, Pd/C
Acetyl (Ac)
Protects: amines as an amide- Put on with
- acetic anhydride or acetyl chloride
- Stable to
- most conditions, very robust
- Removed with
- strong hydrolysis (acid or base, heat)
Alcohols
TBS / TBDMS (tert-Butyldimethylsilyl)
Protects: alcohols as a silyl ether- Put on with
- TBSCl, imidazole, DMF
- Stable to
- bases, oxidants, many reducing agents, Grignard reagents
- Removed with
- fluoride (TBAF) or acid
Bn (Benzyl)
Protects: alcohols as a benzyl ether- Put on with
- NaH, benzyl bromide
- Stable to
- acids and bases
- Removed with
- hydrogenolysis: H₂, Pd/C
THP (Tetrahydropyranyl)
Protects: alcohols as an acetal- Put on with
- dihydropyran, acid catalysis (PPTS)
- Stable to
- bases, nucleophiles, Grignard reagents
- Removed with
- aqueous acid
Acetyl (Ac)
Protects: alcohols as an ester- Put on with
- acetic anhydride, pyridine
- Stable to
- acids, oxidants
- Removed with
- base: K₂CO₃ in methanol or NaOH
Aldehydes and ketones
Acetal (e.g. with ethylene glycol)
Protects: carbonyl groups- Put on with
- diol, acid catalysis, remove water
- Stable to
- bases, Grignard reagents, LiAlH₄, NaBH₄
- Removed with
- aqueous acid
Carboxylic acids
Methyl or ethyl ester
Protects: carboxylic acids- Put on with
- Fischer esterification (alcohol, H⁺)
- Stable to
- mild acids, oxidation
- Removed with
- saponification (NaOH), then acidify
tert-Butyl ester
Protects: carboxylic acids- Put on with
- isobutene, H⁺
- Stable to
- bases, nucleophiles
- Removed with
- acid: TFA
Benzyl ester
Protects: carboxylic acids- Put on with
- benzyl alcohol, H⁺ or benzyl bromide, base
- Stable to
- mild acids and bases
- Removed with
- hydrogenolysis: H₂, Pd/C
Orthogonal protecting groups
Two protecting groups are orthogonal if each can be removed without touching the other. The classic case is peptide synthesis: Fmoc (base) on the chain amine and tert-butyl groups (acid) on side chains, or Boc (acid) next to Cbz (hydrogenation).
Frequently asked questions
What is a Boc protecting group?
Boc (tert-butyloxycarbonyl) protects amines as a carbamate. It goes on with Boc₂O, survives bases and nucleophiles and is removed with acid (TFA or HCl).
What is the difference between Boc and Fmoc?
Both protect amines. Boc comes off with acid, Fmoc with base (piperidine), so they can be used side by side.
Which protecting group for alcohols?
Often silyl ethers such as TBS (removed with fluoride), benzyl ethers (hydrogenolysis) or THP (acid). The choice depends on the conditions that follow.
How do you protect a ketone from a Grignard reagent?
As an acetal, e.g. with ethylene glycol and acid catalysis. Acetals survive bases and Grignard reagents and are cleaved with aqueous acid.