protecting groups

1. Alcohol protection
By kiran khan

2. 1. Definition of protecting groups……………….3
2. Example of protecting groups…………………4,5
3. Types of protecting groups………………. 7 to 8
4. Ether protecting groups…………………12 to 19
5. Silyl ether protecting group……………2o to 31
6. Protection of 1,2 diols……………………32 to 37
7. Hydroxyl as a protecting group………38 to 43

3.  Any chemical entity that is temporarily
reacted with a functional group so as to
protect it from a subsequent reaction is
called the protecting groups

4.  In many preparations of delicate organic compounds, some
specific parts of their molecules cannot survive the required
reagents or chemical environments.
 Then, these parts, or groups must be protected.
 For example,
 lithium aluminium hydride is a highly reactive but useful
reagent capable of reducing esters to alcohols. It will
always react with carbonyl groups, and this cannot be
discouraged by any means. When a reduction of an ester is
required in the presence of a carbonyl, the attack of the
hydride on the carbonyl has to be prevented.

5. • For example,
 The carbonyl is converted into an acetal, which does not react
with hydrides. The acetal is then called a protecting group for
the carbonyl. After the step involving the hydride is complete,
the acetal is removed (by reacting it with an aqueous acid),
giving back the original carbonyl. This step is
called deprotection.

6.  Advantages of the protecting group
 Allows the reaction which would other wise not
possible
 Disadvantages of the protecting groups
 Extra steps
 Lowered yield
 Added mass of protecting group on substrate

7.  Common protecting group
 Alcohol protecting group
 Carbonyl protecting group

8. Amine protecting group
 carboxylic acid protecting group

9. -Ester
- protection
Ether
protection
Ether silyl
protection

11.  Methyl ether
 Not commonly used due to the difficulty of
deprotection Methoxy group can be found in
naturally occurring unusual sugars

BBr3, CH2Cl2

12. Example

13.  Methoxy methane
Formation:
MeOCH2Cl, NaH, THF,
Cleavage:
Me2BBr
HCl/ THF, reflux
CH3COCl, MeOH
• Stable in basic conditions The reagent, MOMCl, is considered
carcinogenic

14.  Tetra hydro pyranal
R-OH O
OROH+, PhH
Formation:
Stable to base
DHP, PPTS, CH2Cl2
Cleavage:
PPTS, EtOH
, MeOH

15.  Mechanism
 Deprotection

16.  Benzyl ether
Formation:
NaH, BnBr, THF/ DMF/ DME
Cleavage:
H2/ PtO2
Li/ NH3 H2/ Pd-C

17.  Benzyl ether
R O H
Deprotection
H2/Pd
Benzyl ether is
stable to base,
mild acid, oxidation
& reduction

18.  P-methoxybenzyl ether
KH, p-Methoxybenzyl chloride, THF
Formation:
Cleavage:
Li/ NH3 H2/ Pd-C

19.  Mechanism

20. Trimethylsilyl
ether
(TMS)
Tertiary-butyl
diphenylsilyl
ether(TBDP
S)
Tertiary-butyl
dimethylsilyl
ether
(TBDMS)
Tri-isopropylsilyl
Ether (TIPS)
R
O
Si
CH3
CH3
CH3
R
O
Si
CH
CH
H3C
CH3H3C
CH
CH3
CH3
CH3
R
O
Si
CH3
CH3
CH3
CH3
CH3
R
O
Si
C2H5
C2H5
C2H5

21.  -Serving as effective protective groups for
alcohols, silyl ethers are used extensively in
laboratory scale synthesis.
 -At least two of the three R’ groups are the
same group, because if all three were
different the silicon atom would be
stereogenic and could give rise to
diastereomers, which would complicate
handling of the compound.
 -TBS, TIPS, TBDPS groups are bulky enough to
selectively protect primary alcohols in the
presence of secondary and tertiary alcohols

22.  Reaction
 Mechanism
 Protection

23. 1. Trimethylsilyl ethers (TMS):

24.  Protection
As to obtain our desire product
We first protect alcohol
desired product
O H
Si
Cl O
Si
H
O
O Et3N
O
Si
O
O H
O
3HC MgBr
OH
OH

25.  Tertiary-butyldiphenylsilyl ether
 (TBDPS)
Properties:
Stable to bases and mild acids
Selective for primary alcohols
Me3Si & i-Pr3Si groups can be selectively
removed in presence of TBS or TBDPS
TBS group can be selectively removed in
presence of TBDPS by acid hydrolysis

26.  Mechanism TBDPS
OH O O
SiO Ot-Bu
Ph
Ph
O
SiO OH
t-Bu
Ph
Ph
OH HO
TBDPS
Imidazol
CuCl2
2H2O
(5
mmol%)
Acetone/H2O
89 %
CuCl2 2H2O
(5 mmol%)
95 % EtOH 60 %
DMF

27.  Tertiary-butyldimethylsilyl ether (TBDMS)
Properties:
Stable to bases and mild acids
Under controlled condition it is
selective for primary alcohols
Formation:
t-Butyldimethylsilyl triflate, base
t-Butyldimethylsilyl chloride, base

28.  Mechanism
Br
OH
CLi
OH
Br
O Li

29.  Mechanism of protection and deprotection
Br
OH Si
Cl
Imidazole Br
O
Si
Li C
O
Si
TBAF
F
O
Si
F
H
OH

30.  Tri-isopropylsilyl ether(TIPS)
 Protection
 Reagents TPSCl, imidazole, DMAP,
CH2Cl2, EtOH, THF
 Example
Me
OMe
OH
CO2t-Bu
OH
TIPSCl, DMAP
DMF
Me
OMe
OH
CO2t-Bu
OTPIS

31.  Protection of diols
R1
HO
R2
OH R3
O
R4
Acid
R1
O
R2
O
R3 R4

32.  Mechanism
R3 R4
O
R3 R4
O
HO OH
R1 R2
OH
R1 R2
R3
R4HO
OH
R1 R2
R3
R4H2O
R1 R2
O O
R4R3
H
R1 R2
O O
R4R3
(H+)
H
H+

33.  Isopropylidenes (acetenoid)
mild aquouse condition
Cleavage:

34.  Mechanism

35.  Cycloalkylidine
R1
HO
R2
OH
Acid
O
R1
O
R2
O
Cyclopentylidenes are slightly easier to cleave than acetonides
Cyclohexylidenes are slightly harder to cleave than acetonides

36.  Benziledine acetal
R1
HO
R2
OH
Acid
CH(OMe)2 CHO
R1
O
R2
O
Ph
1,3-Benzylidene formation is usually favored over 1,2-
Benzylidene
Benzylidenes are usually hydrogenolyed slower than benzyl
ethers or olefins
Cleavage: Acid hydrolysis or hydrogenolysis

37.  Carbonates
Cleavage: Removed with base
Stable to acid & more difficult to hydrolyze than esters
Formation: Im2CO or phosgene or triphosgene
R1
O
R2
O
O
R1
HO
R2
OH
Im2CO

38.  Glycol such as ethyl glycol, propyl glycol etc
are used for the protection of carbonyl
compounds
 Example
 The reversibility of acetal and ketal can be
used for the protection of carbonyls

39.  Hydroxyl as protecting group
 Mechanism for the protection of carbonyl by
1,2 diol

40.  Mechanism for protection of carbonyl by 1,3
diol

41.  Hydroxyl as a protecting group
 Reversibility of acetal and ketal help us to
protect the carbonyl
O
O O
OH OH

42.  For example
 If we want a following conversion given
below What reagent are used for the
catalytic hydrogenation of the group below
O O

43.  If we use a catalytic hydrogenation we does
not get our desired product because there is
a problem if we use a catalytic
hydrogenation then it will reduce both the
carbonyl and the double bond
O OH
H2/Ni

44. Mechanism for ketal
O
H2/Ni
OH
HO
H2
C
CH2
HO
Acidic medium
O O
H2/Ni
O O
H+/H2O
O

45.  Mechanism for Acetal
 Desired product
 But if the reaction is occur then the following
compounds is formed which is not our desired
product
Cl
O
H
NH2
O
HReagent
Cl
O
H
NH2
N
H
H
NH3

46.  Reaction involving the acetal formation in
this case we will get our desired product
O
Cl
H
NH2
O
H
O O
NH2
H
O O
NH3
Hydrolysis
OH OH

47.  http://www.chem-station.com/en/reactions-
2/2014/04/protection-of-12-13-diols-2.html
 http://www.synarchive.com/protecting-
group/Alcohol_Methoxymethyl_acetal
 https://www.clutchprep.com/organic/guide
/protecting-groups
 https://en.wikipedia.org/wiki/Protecting
group