-1-
PROTECTING GROUPS & CARBOHYDRATES NOTES
Protecting Groups
Protecting Groups are introduced onto a Functional Group to block its reactivity under
experimental conditions needed to make modifications elsewhere. The negative aspect
of this is that taking them on/off results in a loss of yield.
Criteria for a good protecting group:
• Quantitative yield at desired site.
• No alteration to the rest of the molecule.
• Preferably no new stereogenic centres.
• Not broken down in subsequent stages.
• Does not cause side reactions.
• Removable under specific conditions.
Also things like cost / toxicity etc.
Reaction Conditions should be available that remove one type of protecting group,
leaving others intact. This is an Orthogonal Strategy. We may require a degree of fine-
tuning to allow selectivity (graduation of lability) so this is important. A good example is
the effect of silyl protection bulk on ease of removal.
Ethers / Alcohols
Benzyl
ON = base then Benzyl Chloride.
OFF = hydrogenation (Pt/H2).
Paramethoxybenzyl (PMB)
ON = same as benzyl, except use (p-OMe)Benzyl Chloride.
OFF = DDQ or CAN (NH4)2Ce(NO3)6, i.e. one electron donation (SET).
Silyl
ON = silyl chloride, base (useful to soak up base). Often a nucleophilic catalyst
is needed for bulkier silyls, such as imidazole.
OFF = F- or acid, via Ates Complex. Based on strong Si-O/Si-F bonds.
Selectivity – 1 > 2o > 3o alcohols, i.e. based on sterics (accessibility and lability).
o
Specific examples are:
TMS – Me3Si – easy to add/remove, but sometimes too easy. Vulnerable to oxidation
conditions. Good for temporary protection.
TES – Et3Si – useful in that easier to remove relative to other bulkier Si protecting groups
Î selectivity. Used particularly in OH Æ =O oxidation (CrO3, Swern), as these
conditions remove TES but not bulkier silyls.
TPS – Ph3Si – very easy to remove in basic conditions but slowed in acid (between TES
and TBS, see below). Also very bulky Î diastereocontrol, although less good at this
than TBS.
TBS – tBuMe2Si – 1o > 2o, but doesn’t protect 3o alcohols unless TBSOTf + pyridine is
used. It is cleaved by AcOH, ArSO3H and F-.
TBDPS – tBuPh2Si – more extreme versions of TBS. Very tolerant to acid conditions, but
not basic.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
TIPS – iPr3Si – the most stable to base/nucleophilic conditions.
Silyls will also protect aldehydes / ketones by trapping the enol ether. Si-N bond is weak,
so this does not work for amines.
Allyl
ON = allylic bromide + base.
OFF = HgX2 + H2O/H+ (hydrolysis). The C=C bond complexes to the Hg. Strong
base can also be used instead (tBuOK), or oxidative cleavage (OsO4).
Trityl
ON = Ph3C-Cl. Attaches to primary alcohols only. SN1 mechanism.
OFF = Weak acid. It resists base, but is easily removed in acid due to the
stability of the carbocation. HCO2H will cleave it in the presence of other acid-sensitive
protecting groups.
Acetals
Acetonide
ON = acetone/H+(cat), Me2C(OMe)2.
OFF = aqueous H+.
See Carbohydrates Notes for the mechanisms for this.
Benzylidene
ON = PhCHO / H+(cat), or PhCH(OMe)2.
OFF = aqueous H+, or hydrogenation, or reductive opening.
See Carbohydrates Notes for the mechanisms.
Tetrahydropyran (THP)
ON =
OFF = Aqueous acid (Acetal Hydrolysis).
Methoxymethyl Ester (MOM)
ON = MeOCH2Cl + NiPr3. Adds to 1o and 2o only. 3o requires MeOCH2I. These
reagents are highly toxic, so there are some variants. Borderline SN1/SN2 mechanism.
OFF = strong H+. Can be a problem for the rest of the molecule. Lewis Acid /
Nucleophilic combinations are more selective.
2-methoxyethoxy methyl, MEM
Lewis Acid labile. More SN1 character. Methyl ethers are good due to reluctance to form
Me+.
2-trimethylsilylethoxymethyl, SEM
Me3SiCH2CH2OCH2X. Protect similar to other acetals, but deprotection is orthogonal as
it is the same as silyl ethers (i.e. H+ or F-).
Esters
Acetate
ON = Ac2O or AcOCl + base (pyridine usually).
OFF = base (-OMe).
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
PROTECTING GROUPS & CARBOHYDRATES NOTES
Protecting Groups
Protecting Groups are introduced onto a Functional Group to block its reactivity under
experimental conditions needed to make modifications elsewhere. The negative aspect
of this is that taking them on/off results in a loss of yield.
Criteria for a good protecting group:
• Quantitative yield at desired site.
• No alteration to the rest of the molecule.
• Preferably no new stereogenic centres.
• Not broken down in subsequent stages.
• Does not cause side reactions.
• Removable under specific conditions.
Also things like cost / toxicity etc.
Reaction Conditions should be available that remove one type of protecting group,
leaving others intact. This is an Orthogonal Strategy. We may require a degree of fine-
tuning to allow selectivity (graduation of lability) so this is important. A good example is
the effect of silyl protection bulk on ease of removal.
Ethers / Alcohols
Benzyl
ON = base then Benzyl Chloride.
OFF = hydrogenation (Pt/H2).
Paramethoxybenzyl (PMB)
ON = same as benzyl, except use (p-OMe)Benzyl Chloride.
OFF = DDQ or CAN (NH4)2Ce(NO3)6, i.e. one electron donation (SET).
Silyl
ON = silyl chloride, base (useful to soak up base). Often a nucleophilic catalyst
is needed for bulkier silyls, such as imidazole.
OFF = F- or acid, via Ates Complex. Based on strong Si-O/Si-F bonds.
Selectivity – 1 > 2o > 3o alcohols, i.e. based on sterics (accessibility and lability).
o
Specific examples are:
TMS – Me3Si – easy to add/remove, but sometimes too easy. Vulnerable to oxidation
conditions. Good for temporary protection.
TES – Et3Si – useful in that easier to remove relative to other bulkier Si protecting groups
Î selectivity. Used particularly in OH Æ =O oxidation (CrO3, Swern), as these
conditions remove TES but not bulkier silyls.
TPS – Ph3Si – very easy to remove in basic conditions but slowed in acid (between TES
and TBS, see below). Also very bulky Î diastereocontrol, although less good at this
than TBS.
TBS – tBuMe2Si – 1o > 2o, but doesn’t protect 3o alcohols unless TBSOTf + pyridine is
used. It is cleaved by AcOH, ArSO3H and F-.
TBDPS – tBuPh2Si – more extreme versions of TBS. Very tolerant to acid conditions, but
not basic.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
TIPS – iPr3Si – the most stable to base/nucleophilic conditions.
Silyls will also protect aldehydes / ketones by trapping the enol ether. Si-N bond is weak,
so this does not work for amines.
Allyl
ON = allylic bromide + base.
OFF = HgX2 + H2O/H+ (hydrolysis). The C=C bond complexes to the Hg. Strong
base can also be used instead (tBuOK), or oxidative cleavage (OsO4).
Trityl
ON = Ph3C-Cl. Attaches to primary alcohols only. SN1 mechanism.
OFF = Weak acid. It resists base, but is easily removed in acid due to the
stability of the carbocation. HCO2H will cleave it in the presence of other acid-sensitive
protecting groups.
Acetals
Acetonide
ON = acetone/H+(cat), Me2C(OMe)2.
OFF = aqueous H+.
See Carbohydrates Notes for the mechanisms for this.
Benzylidene
ON = PhCHO / H+(cat), or PhCH(OMe)2.
OFF = aqueous H+, or hydrogenation, or reductive opening.
See Carbohydrates Notes for the mechanisms.
Tetrahydropyran (THP)
ON =
OFF = Aqueous acid (Acetal Hydrolysis).
Methoxymethyl Ester (MOM)
ON = MeOCH2Cl + NiPr3. Adds to 1o and 2o only. 3o requires MeOCH2I. These
reagents are highly toxic, so there are some variants. Borderline SN1/SN2 mechanism.
OFF = strong H+. Can be a problem for the rest of the molecule. Lewis Acid /
Nucleophilic combinations are more selective.
2-methoxyethoxy methyl, MEM
Lewis Acid labile. More SN1 character. Methyl ethers are good due to reluctance to form
Me+.
2-trimethylsilylethoxymethyl, SEM
Me3SiCH2CH2OCH2X. Protect similar to other acetals, but deprotection is orthogonal as
it is the same as silyl ethers (i.e. H+ or F-).
Esters
Acetate
ON = Ac2O or AcOCl + base (pyridine usually).
OFF = base (-OMe).
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
