Protecting Groups

What are protecting groups?

Groups, which are temporarily attached to a functional group
Make these functional groups not to react under certain reaction
conditions in subsequent steps.
Cleaved after its job is done

Why do you need protecting groups?

When a molecule has more than one functional group, then there is a
likely possibility that functional groups interfering with each other
while carrying out a reaction.

When principles of selectivity can’t be applied, then protection of one

functional group is really necessary to carry out a reaction on the
other functional group.
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1
 Protecting Groups
Why do you need protecting groups?

O O

CO2Et CH2OH

O O

O O

CO2Et CH2OH
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2
 Protecting Groups
Drawbacks

1. Two additional steps are required.

2. One for the introduction of the protecting group and the other for
removing it.

3. So, more the number or protecting groups in your synthetic

scheme, more the number of steps.

The best protecting group is “NO PROTECTING GROUP”

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3
 Protecting Groups
What is orthogonal protecting group strategy?

When more than one functional group of similar type, with very little
difference in terms of reactivity, present in the molecule, selective
protection of one can be achieved in the presence of other by taking
advantage of steric effects, stereoelectronic effects etc.,

The development of such orthogonal protecting group strategies

makes it possible to remove one set of protecting groups, in any
order, using reagents and conditions that do not affect the protecting
groups in other sets.

This orthogonal protecting group strategy is regularly utilized in the

synthesis oligosaccharides where more number of hydroxyl groups
with subtle difference in reactivity are present.
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4
 Protecting Groups
Types of Protecting Groups

Permanent: These are stable protecting groups, survives many steps

in a long synthetic route (early introduction & late removal). These
protecting groups are used for functional groups which require no
manipulation for most of the steps

Temporary: These protecting groups (as the name suggests) should be

selectively installed and removed as and when required without
affecting the permanent protecting groups.

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5
 Protecting Groups
Criteria for selecting protecting groups

Should be cheap & commercially available

Should be easily introduced under milder conditions

Should not create any additional stereocenters

Should be stable throughout the reaction, work up and purification

Should be easily removed under milder conditions

Byproducts should be easily separated from the required product

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6
 Functional Groups

Hydroxy

Functional
Groups

Carbonyl Amines

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7
 Hydroxyl Group

Primary

Phenols Secondary

Hydroxyl

DIols Tertiary

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8
 Carbonyl Group

Carboxylic acids

Carbonyl

Aldehydes Ketones

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 Amines

Aliphatic Primary

Amines

Aliphatic Secondary Aromatic

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 Protecting Groups for Alcohols

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12
 PG for Alcohols
Introduction of protecting groups

R O H + X PG R O PG + HX

Removal of protecting groups

R O PG + HY R O H + Y PG

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12
 PG for Alcohols

Alkyl Ethers

Silyl Ethers Alcohols Benzyl Ethers

Esters

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13
 PG for Alcohols

ROMe, ROMOM, ROMEM, ROBOM, ROTHP, ROEE

Alkyl
ethers

ROBn, ROPMB ROTr

RONAP, ROMeTr, Benzyl Esters ROAc, ROAcCl, ROBz,
Alcohols
RO-o-NO2Bn, ethers ROPiv, ROCOCF3
RO-p-NO2Bn,
Silyl
ethers

ROTMS, ROTES ROTIPS, ROTBS, ROTBDPS

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14
 Alkyl Ethers

Methyl Ether

EE Ether MOM Ether

Alkyl
Ethers

THP Ether MEM Ether

BOM Ether

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15
 Benzyl Ethers

Benzyl Ether

o-NO2Bn Ether PMB Ether

Benzyl
Ethers

OMe-Tr Ether NAP Ether

Tr Ether

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16
 Silyl Ethers

TMS Ether

TBDPS Ether TES Ether

Silyl
Ethers

TBDMS Ether TIPS Ether

IPDMS Ether

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17
 Esters

Acetate

Pivalate ester Chloroacetate

Esters

Trifluoroacetate Dichloroacetate

Trichloroacetate

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18
 Esters
Benzoate

Troc Boc

Esters

Alloc CBz

Fmoc

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19
 1,2-Diols

Acetonide

Cyclic carbonate Cycloalkylidene

1,2-Diols

Di-t-Butylsilylene Benzylidene

p-Methoxybenzylidene

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20
 Alkylethers

NaH, MeI, THF

OR
Ag2O, MeI NaH, CH3OCH2Cl, THF

OR OR

CH2N2 (Phenols) DIEPA, CH3OCH2Cl, THF

ROMe Alcohols ROMOM

BBr3, DCM HCl, THF

OR OR

HCl, ROH AcCl, EtOH

OR
TMSCl/NaI

Difficult to cleave except for phenols

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 Alkylethers

Benzyloxymethyl ether (BOM)

NaH, CH3OCH2CH2OCH2Cl, THF
OR
DIPEA, PhCH2OCH2Cl, DCM
DIPEA, CH3OCH2CH2OCH2Cl, THF

ROBOM Alcohols ROMEM

H2, Pd-C, EtOH ZnBr2
OR OR

Li, Liq. NH3 TiCl4

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 Alkylethers

, PPTS, DCM
O O , PTSA, DCM

ROTHP Alcohols ROEE

PPTS, EtOH PPTS, EtOH

OR OR

Amberlyst H-15, MeOH Amberlyst H-15, MeOH

Creates one more chiral center

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 Benzylethers
NaH, BnBr, THF
OR
KH, BnCl, THF NaH, PMBCl, THF

OR OR
NH NH

Cl3C OBn , CSA Cl3C OPMB , CSA

ROBn Alcohols ROPMB

H2, Pd-C, EtOH H2, Pd-C, EtOH

OR OR

Li, Liq. NH3 Li, Liq. NH3

OR OR

BBr3, DCM DDQ, MeOH

OR
Benzyl ethers are stable
CAN, MeOH

12/30/2024
 PMB ethers
NaH, THF
RO
ROH OMe
Cl

MeO

PMP
OH OPMB DDQ O O
R DCM, MS
R

CAN DIBAL-H
OR
DDQ
PMBO OH
OH OH
R
R

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 Benzyl Ethers
Selective for primary alcohols

Highly sensitive to acid

2-Naphthylmethyl ether (NAP)

Cl
NaH, , THF
Ph3CCl, Et3N, THF

RONAP Alcohols ROTr

H2, Pd-C, EtOH Mild Acid R1
OR
Li, Liq. NH3

NAP ethers could be cleaved R2 Tr

selectively in the presence of Bn
ethers

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 Nitrobenzyl ethers
o-Nitrobenzyl ethers p-Nitrobenzyl ethers

Cl Cl
NaH, , THF NaH, , THF
NO2 O2N

RO-oNb Alcohols RO-pNb

Photolysis @ 320nm H2/Pd-C

OR
DDQ
OR
Electrochemical
o-Nitrobenzyl ethers are cleaved conditions
under photochemical conditions

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 Protection of Phenols
Most of the protecting groups used for alcohols are applicable for
phenols.
Common phenolic protecting groups are:
OMe OtBu O OBn

Methylether t-Butylether Allylether Benzylether

R1 O O
R2
Si R
O R3 O R O O O OR

Silylethers Phenyl Phenyl

esters carbonates Acetals
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 Methyl Ethers
Protection

NaOH, Me2SO4
OH OR OMe
K2CO3, MeI

OR
CH2N2
Deprotection

BBr3, DCM
OMe OR OH

EtSNa, DMF

OR
TMSI
OR
HCl, MeOH
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 TMS and TES Ethers
TMS Ether TES Ether

Easy to introduce Easy to introduce

Used for transient protection More stable than TMS

Very labile to acid and water Selectively cleavable

TMSCl, Py, DMAP TESCl, Py, DMAP

OR OR
TMSCl, Im, DMAP, DCM TESCl, Im, DMAP, DCM
OR OR
TMSOTf, DIPEA, DCM TESOTf, DIPEA, DCM
ROTMS Alcohols ROTES
AcOH/H2O, 15 h
dil. Acid OR
F- source
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 TIPS and TBS Ethers
TIPS Ether TBS Ether

Easy to introduce Selective protection of 1o alcohols

More stable than TMS/TES Stable to base and mild acid

TBSOTf is a good reagent for 2o

alcohols
TIPSCl, Py, DMAP
TBDMSCl, Py, DMAP
OR OR
TIPSCl, Im, DMAP, DCM TBDMSCl, Im, DMAP, DCM
OR OR
TIPSOTf, DIPEA, DCM TBDMSOTf, DIPEA, DCM
Alcohols ROTBS
ROTIPS
AcOH/H2O, 15 h Fluorides like
OR TBAF, KF, HF.Py, CsF
F- source
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 TBDPS ethers
TBDPS Ether
Stable to base and acid

Selective for primary alcohols

TMS/TES/TIPS can be selectively removed in the presence of TBS/TBDPS

TBS can be selectively removed in the presence of TBDPS by acid

TBDPSCl, Py, DMAP
OR
TBDPSCl, Im, DMAP, DCM
OR
TBDPSOTf, DIPEA, DCM
Alcohols ROTBDPS
Fluorides like
TBAF, KF, HF.Py, CsF
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 Esters
O R1
R OH R
O
Formation: Activated acid, base, DMAP, solvent

Activated acid: Acid Chlorides, Anhydrides, Activating agents

Acid chloride: SOCl2, Oxalylchloride, PCl5

Activating agents: CDI, DCC, HOBT, NHS, PySSPy, Mukaiyama’s reagent

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 Acetates
O R1
R OH R
O

Properties: Stable to acid and mild base

Not compatible with strong nucleophiles
such as organometallic reagents

Formation: Ac2O, pyridine

Acetyl chloride, pyridine

Cleavage: K2CO3, MeOH, reflux KCN, EtOH, reflux

NH 3 , MeOH LiOH, THF, H2
Enzyme hydrolysis (Lipase)

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 Pivaloates
O C
R OH R
O

Properties: Selective for primary alcohols

Removed with mild bases

Formation: t-Butylacetyl chloride, Py

t-Butylacetic anhydride, Base

Cleavage: K2CO3, MeOH

LAH, Et2O

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 Chloroacetates
O
R OH R Cl
O

Properties: Removed with Zn dust or thiourea

Formation: Chloroacetyl chloride, Base

Cleavage: Zn dust
Thiourea

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 Trifluoroacetates
F
F
O
R OH R F
O

Properties: Removed with base

Formation: Trifluoroacetyl chloride, Base

Trifluoroacetic anhydride, Base

Cleavage: K2CO3, MeOH

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 Benzoates

O
R OH R
O

Properties: More stable than acetates wrt hydrolysis

Formation: Benzoyl chloride, Base

Benzoyl cyanide, Base

Benzoic anhydride, Base

Cleavage: K2CO3, MeOH

KCN, MeOH

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 Protecting Groups for Diols

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40
 1,2-Diols
R2 R3
OH Aldehyde or O O
R1
R Ketone, H+
OH R R1

Isopropylidenes (acetonides)

HO OH Acid O O

R1 R2 Acetone or
R1 R2
OMe OMe
or
OMe

Cleavage Mild aqueous acid

1,2-acetonide formation is usually favored over 1,3-acetonides

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 1,2-Diols
Cycloalkylidene ketals

n
HO OH Acid O O

R1 R2
or R1 R2

O O

Cyclopentylidenes are slightly easier to cleave than acetonides

Cyclohexylidenes are slightly harder to cleave than acetonides

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 1,2-Diols
Benzylidene acetals
Ph
HO OH Acid O O

R1 R2 CH(OMe)2 CHO
R1 R2

or

Cleavage: Acid hydrolysis or hydrogenolysis

1,3-Benzylidene formation is usually favored over 1,2-Benzylidene

Benzylidenes are usually hydrogenolyed slower than benzyl ethers or

olefins
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 1,2 & 1,3-Diols
Benzylidene acetals & Acetonides

Ph
OH
PhCHO O
O
CH2OH ZnCl2

PhCHO
OH
CH2OH ZnCl2 O Ph
O

OH
Acetone TrO
TrO
O
PPTS, CuSO 4 O OH
OH OH

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 1,2-Diols
p-Methoxybenzylidene acetals
Ph
HO OH Acid O O

R1 R2 CH(OMe)2 CHO
R1 R2

or

OMe OMe

Cleavage: Acid hydrolysis or hydrogenolysis or DDQ or CAN

Hydrolyzed about 10 times faster than regular benzylidenes

12/30/2024
 Other Reactions
Ph
TiCl4 HO OBn
O O
NaCNBH3
MeO2C CO2Me
MeO2C CO2Me

O Br
O NBS
Ph O Ph O
O OMe O OMe
HO CH3CN HO
OH OH

PMP
OH OPMB DDQ PMBO OH
O O DIBAL-H
R DCM, MS R
R

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 1,2-Diols
Cyclic Carbonates
O
HO OH Im2CO O O
R1 R2
R1 R2

Formation: Im2CO or phosgene or triphosgene

Cleavage: Removed with bases

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 Protecting Groups for Carbonyls

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48
 PG’s for Aldehydes/Ketones

O O O O O O O O
R1 R2 R1 R2 R1 R2 R1 R2

Dimethyl 1,3-Dioxolane 1,3-Dioxane 2,2-Dimethyl

acetal 1,3-dioxane

S S S S O S
S S
R1 R2 R1 R2 R1 R2
R1 R2
S,S-Dimethyl 1,3-Dithiolane 1,3-Dithiane 1,3-Oxathiolane
thioacetal

Order of Reactivity
Aldehydes > acyclic ketones = cyclohexanones > cyclopentanones >
α,β-unsaturated ketones = α,α-substituted ketones > aromatic ketones
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 Dimethyl acetals/ketals

O
O O
R1 R2 R1 R2

Formation Cleavage

1. MeOH, Dry HCl 1. Acetone, PTSA

2. Sc(OTf)3, CH(OMe)3 2. TFA, CHCl 3 , H2O

MeO OMe
3. , PTSA

4. TMSOMe, TMSOTf, DCM

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 Dimethyl acetals/ketals

O
O
Acetone
O
D-Glucose
ZnCl2
HO O
O

MeO OMe
OH OH , DME O OH
HO O
OH O
SnCl 2
OH OH OH O

TiCl 4 OMe
O O O
MeOH, Et 3N OMe

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 1,3-Dioxolones/1,3-Dioxanes

O
O O O O O O
R1 R2 R1 R2 R1 R2 R1 R2

Formation Cleavage
n
HO OH , Toluene, PTSA 1. Acetone, PPTS, H2O, Heat

n 2. 1M HCl, THF
TMSO OTMS , TMSOTf, DCM
3. Me2BBr, DCM, -78 oC
-78 oC

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 1,3-Dioxolones/1,3-Dioxanes
O O
O O
O O
HO OH OH OH
PTSA, Toluene PTSA, Toluene

O O
O
HO OH

O PTSA, Toluene O

Double bond increases the electron density at the carbonyl

carbon of the Ɑ,ℬ-unsaturated ketones

HO OH
O
O PTSA, Toluene
O
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 1,3-Dioxolones/1,3-Dioxanes

TMSO OTMS
O
O TMSOTf, DCM
-78 oC O

This procedure developed by Noyori, at lower temperature, the

double bond doesn’t migrate.

O H O O HO
O
HO OH

PTSA, Toluene
CH3 CH3

Steric hindrance could be used to selectively protect one of the

carbonyl groups

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 1,3-Dithiolones/1,3-Dithianes
HS SH
S
O BF3.OEt2, DCM
-20 oC S

Since thioacetals are quite stable towards hydrolysis, no need to

remove water from the reaction mixture.

Double bond migration is also not observed as this reaction is

done at a lower temperature

S S
TFA S
MeO S O
O
OHC
MeO O O

Selective removal of acetal is possible in the presence of

thioacetal
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 1,3-Dithiolones/1,3-Dithianes

Ra-Ni, H2
HgCl2, CaCO3 S
EtOH
O Acetone S

Cleavage of dithianes and dithiolanes:

Hg(ClO) 4 , MeOH, CHCl 3 , 25 oC

NBS, acetone, 0 oC
I2, DMSO
CAN, aq. CH 3 CN
m-CPBA, Ac2O
DDQ, aq. CH 3 CN

12/30/2024
 1,3-Dithioxolones/1,3-Dithianes

1,3-dioxolanes and 1,3-dioxanes can be readily converted into

1,3-dithiolanes and 1,3-dithianes

O O SH SH S S
BF3.Et2O

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 1,3-Dithioxolones/1,3-Dithianes
Fluoride cleavable ketal

O O
LiBF4
O O O
O
O
Me3Si

Base cleavable ketal

HO SO2Ph SO2Ph
O OH O
DBU, DCM
O O
R1 R2 pTSA R1 R2
R1 R2

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 PGs for Carboxylic Acids
O O O O
Ph
R OMe R O R O R O
tButyl Ester Allyl Ester Phenyl Ester
Methyl Ester

O O R O O NO2
R
Bn Si
R O R O R R O CCl3 R O
Benzyl Ester Silyl Ester Halo Ester o-Nitrobenzyl Ester

OR TMS
OR O O O N
R OR TMS
R O R O R O
Orthoester TMS ethyl
Ester SEM Ester 1,3-Oxzoline

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 PGs for Carboxylic Acids
1. Alkyl esters:

Formation: Fischer esterification (RCOOH + R’OH + H + )

Acid chloride + ROH, pyridine
t-Butyl esters: Isobutylene & acid
Methyl esters: Diazomethane

Cleavage: LiOH, THF, H2O

Enzyme hydrolysis
t-Butyl esters are cleaved with aq. acid
Bu2SnO, PhH, reflux

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 Alkyl Esters
DCC

BnOH OBn
OH

DCC O
O

Mitsunobu Reaction

EtOH, Ph3P OEt

OH

DEAD, Et2O O
O

H2SO4, Cat O
CO2H
OR O
1, MsCl, Py
2. tBuOH, Et3N
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 Aryl Esters
Due to steric hindrance, BHT and BHA do not react with
organometallic reagents

MeO OH MeO OH

BHT BHA

O O nBuLi nBu O
BHT, nBuLi

nBu Cl nBu OBHT nBu OBHT

12/30/2024
 Silyl Esters & Oxazolines
Bulky silyl esters do not react with organometallic
reagents; fluorides are required to hydrolyse

OH iPr3SiCl OSiiPr3

O Im, THF O

Oxazolines are stable to organometallic reagents,

reducing agents like LAH etc.,

OH H2N OH O

O Toluene, N
Heat

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 PGs for Amines
Introduction of protecting groups

Unlike alcohols, it is difficult to protect amines through alkylation

R1
Protection Quarternary
R NH2 R NH + R N +
through R1 R1
alkylation

Primary and secondary amines are prone to oxidation

NH bonds undergo metallation on treatment with organometallic

reagents

Because of the presence of the lone pair of electrons, Nitrogen

could be protonated/alkylated.
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63
 PGs for Amines
Best ways to protect amines

It should be protected in such a way that further alkylation doesn’t

take place

To make the lone pairs less reactive, it is better to attach a carbonyl

group
H
N R1
R NH 2 R
O
H
N O
R NH 2 R R1
O

Amides could be cleaved by acids

Carbamates could be cleaved by a variety of reagents, depending

on the nature of the carbamates
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64
 PGs for Amines
O O O O
R R R R
N Me N CF3 N OMe N O
H H H H
Methyl tButylcarbamate
Methyl amide Trifluoromethyl
amide carbamate (Boc)

O SiMe3 O
O
R R
N O CCl3 R N O
H N O H
Trichloroethyl H
Trimethylsilylethyl Allyl carbamate
carbamate (Troc) (Alloc)
carbamate (Teoc)

O Ph
R O
N O
H R
Benzylcarbamate N O
H
(CBz) 9-Fluroenylmethyl
carbamate (Fmoc)
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 Amides
O
R
N R1
H
Amides

Basicity of nitrogen is reduced; so electrophilic attack on the

nitrogen is reduced
Amides are stable to hydrogenation, oxidation, nucleophiles &
organometallic (except organolithium) reagents

O
R
R1COCl, Py N R1
R NH 2 H
Amides
H+, H2O

12/30/2024
 Carbamates
O
R
N OR1
H
Alkyl
carbamates

Carbamates are like amides and so can’t act as a nucleophile

Carbmates are stable to oxidation and aqueous bases though it may

react with reducing agents

O O
R
Cl OR1 N OR 1
R NH 2 H
Carbamates
K2CO3, MeOH

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 Benzyl carbamates (Cbz or Z)
O
O
Cl OBn R H2/Pd-C
R NH2 N OBn R NH2
Base H ROH

Formation: BnOCOCl, Na2CO3, H2O

(BnOCO)2O, dioxane, H2O

Cleavage: H2/ Pd-C

H2/ Pd-C, NH3
Pd-C, HCOONH 4
BBr3, DCM
KOH, MeOH

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 tButyloxycarbonyl (Boc)
O
O
Cl O R HCl
R NH2 N O R NH2
OR H ROH
(Boc)2O
Base

Formation: (Boc)2O, NaOH, H2O, 25 oC

(Boc)2O, TEA, MeOH/ DMF

BocN3, DMSO

Cleavage: 3M HCl, EtOAc

TFA, PhSH, DCM
AcCl, MeOH
CAN, CH3CN

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 9-Fluroenylmethyloxy carbonyl (Fmoc)

O
O N
Cl O H
R NH2 R R NH2
N O
Base H

Formation: Fmoc-Cl, NaHCO 3 , aq. Dioxane

Fmoc-OC6F5, NaHCO 3 , acetone

Cleavage: Amine bases

Piperidine, morpholine, diisopropylethyl amine
TBAF, DMF

12/30/2024
 Allyloxycarbonyl (Alloc)
O
O
Pd(0)
Cl O R R NH2
R NH2 N O Et3SiH
Base H

Formation: CH 2 =CHCH 2 OCOCl, py

(CH 2 =CHCH 2 OCO) 2 O, DCM

Cleavage: Pd(Ph3P)4, TBTH, AcOH

Pd(Ph3P)4, Dimedone, THF

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 Trichloroethyloxycarbonyl (Troc)
O CCl3
O CCl3
Cl O R Zn Dust
R NH2 N O R NH2
Base H

Formation: Cl 3 CCH 2 OCOCl, Py or aq. NaOH

Cleavage: Zn, THF, H2O, pH= 4.2

Zn-Pb couple, 4:1 THF/ 1M NH4OAc

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 Trimethylsilylethyloxycarbonyl (Teoc)
TMS
O TMS
O
Cl O F-
R R NH2
R NH2 N O
Base H

Formation: TMSCH2CH2OCOCl (Teo-Cl) or Teoc-N3

Teoc-OC6H4-4-NO 2 , NaOH
Teoc-OSu, TEA

Cleavage: TBAF, CH3CN

HF, Py, THF

KF, CH3CN

TAST, CH3CN

12/30/2024
 Examples
CO2H CO2H
(Boc)2O
NH2 Im, THF NHBoc

Boc OAc H OAc

N N
AlCl3

OTBS DCM OTBS

O
NH2
HN O
Pd(OAc)2
CO2Me
CO2Me
Et3N, Et3SiH

12/30/2024