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Topic 4 - Protecting Group

Here are three potential examples of using protecting groups: 1. A chemist wants to selectively oxidize an alcohol in a molecule containing both a primary and secondary alcohol. They protect the secondary alcohol as a silyl ether, then oxidize the primary alcohol to a carbonyl. After the desired reaction, they remove the silyl protecting group to obtain the final product. 2. A synthetic route requires reducing an ester to an alcohol, but the molecule also contains an aldehyde. To prevent reduction of the aldehyde, it is first protected as an acetal. After ester reduction, the acetal is removed to give the final product containing both alcohol and aldehyde functional groups. 3. The target molecule

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200 views

Topic 4 - Protecting Group

Here are three potential examples of using protecting groups: 1. A chemist wants to selectively oxidize an alcohol in a molecule containing both a primary and secondary alcohol. They protect the secondary alcohol as a silyl ether, then oxidize the primary alcohol to a carbonyl. After the desired reaction, they remove the silyl protecting group to obtain the final product. 2. A synthetic route requires reducing an ester to an alcohol, but the molecule also contains an aldehyde. To prevent reduction of the aldehyde, it is first protected as an acetal. After ester reduction, the acetal is removed to give the final product containing both alcohol and aldehyde functional groups. 3. The target molecule

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zatty kim
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© © All Rights Reserved
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+

PROTECTING GROUP
+ What is protecting group?
n Protecting groups are groups of atoms that are attached to a
functional group to mask it from competitive undesired
reactions and later be removed from that functional group.

protecting deprotecting

n Advantages: Allows reactions that otherwise would not be


possible

n Disadvantages: extra steps (at least 2 - protection and


deprotection), lowered yield, low atom economy, added mass
of PG on substrate.
+
What are the best PG?

n Considerations:
1. protecting group and both protection / deprotection
sequences must be compatible with all other desired
steps and other functional groups.
2. Cheap & commercially available
3. Easy & efficient introduction
4. Should not create any stereogenic center
Stable throughout reaction, work-up & purification
5. Efficient removal: by-products of the removal should be
easily separated
How the
PG works ?
+
The problem of using PG
n Ether can protect a hydroxyl group as an ether without
worrying about it being affected by reactions

n theres just one problem: ethers require very harsh


conditions in order to break (hydroiodic acid, HI)

n Solution: instead of making a typical ether (e.g. forming an O-


C bond), we form asilylether (i.e. make an O-Si bond, not an
OC bond). Itseven easier to form thana normal ether

n the most common silyl ether used is trimethylsilyl (TMS)


although there are others [Generally, the bulkier the groups
around silicon, the harder it is to cleave the OSi bond]
+
Type of Protecting Group (PG)
n Hydroxyl PG
1. Silyl ether (R-O-Si-R)
2. Acetal (RO-CH2-OR)
3. Cyclic acetal (RO-CH2-O-Cy)
4. Ether (RO-R)
5. Esther (RC-OR
6. Cyclic acetal

n Ketone and aldehyde PG


1. Cyclic acetal
2. thioacetal

n Amines PG
1. Alkyl
2. Amide
3. Sulfonamide

n Amides
+Type of Hydroxyl PG
1. Silyl ether protecting group
n The alcohol group was protected and converted into silyl
ether group

n Few types of silyl ether group:

Trimethylsilyl Triisopropylsilyl Tert-butyldimethylsilyl [2-(trimethylsilyl)


(TMS) (TIPS) (TBS or TBDMS) ethoxy]methyl (SEM)
Silyl ether protecting group
Formation (To protect ): Cleavage (Deprotect):

(CH3)3SiCl
Example 1: Using silyl ether to protect OH group

Step 1: Protect OH group


Step 2: Perform reaction
Step 3: Deprotection OH group
Example 2

Step 1: Protect OH group


Step 2: Perform reaction
Step 3: Deprotection OH group
CHM 624 Final exam question Dec 2014
+
Type of Hydroxyl PG
2. acetals

Formation: Cleavage:
+Type of Hydroxyl PG
3. Cyclic acetals

Tetrahydropyranyl ether (THP)


Type of Hydroxyl PG
4. Ethers

Formation: Cleavage:
+Hydroxyl PG
5. Ester
+Hydroxyl PG
6. Diol Protecting
n All ROH protecting groups work, but 1,2- or 1,3- can be
protected in unique ways.
+
+ The stability of PG
n When more than one alcohol exist, the primary alcohols
(least sterically hindered) will be first protected, then
secondary alcohols (more sterically hindered) and finally
tertiary alcohols

nOHExample 1:
1$equiv.$DHP THP
OH 1$equiv.$DHP
OTHP OTHP
H $$$$$$$$H+ OH
OH $$$$$$$$H+ OH

PCC PCC

H3O+ H3O+
OH OH
OTHP
OH OTHP
H OH
O O

THP
2$equiv.$DHP
n Example 2: HO OH $$$$$$$$H+ THPO OH
OH OTHP
+
n If the oxidation is targeted at primary alcohol, then the
secondary alcohol also should be protected.

n protect both primary and secondary alcohol with a


different protecting group, and deprotect the primary
alcohol, followed by oxidation on primary alcohol

n Using TMS-Cl, Et3N first and then THP. H+ allows you to


remove the TMS group easily with F-, thus allowing the THP
to stay in place:

OH 1$equiv.$TMS.Cl OTMS
OH $$$$$$$$NEt3 OH

DHP,$H+
THP

O
pcc HF
OH OTMS
H
H3O+ OTHP OTHP
OH
+
n If the same protecting group presence on both alcohols,
deprotection occur on both group which cannot be selective

OH 2$equiv.$DHP OTHP
OH $$$$$$$$H+ OTHP

H3O+

OH
OH
+ 21

vEase of cleavage is as follows


v Acidic condition
TMS > TES > TBDMS > TIPS > TBDPS

v Basic condition
TMS > TES > TBDMS = TBDPS > TIPS
+Ketone and aldehyde PG
1. Acetal

Formation:

Cleavage:

The cleavage of acyclic


acetals is easier than of
cyclic acetals
+ Examples 1:
Examples 2:

remove the
protecting group

protect the ketone


as an acetal reduce the ester to
the primary alcohol.
Examples 3:
n If both aldehyde and ketone presence, the aldehyde will be
protected and react with 1,2 or 1,3-diol because aldehyde
are more reactive than ketone.
+Ketone and aldehyde PG
2. Thioalacetal

Formation:

Cleavage:
+Amines PG

n The most common to protect amine is by convert it


to the carbamate formed

n Amines also may be protected as:


N-alkylation (not commonly used)
N-acylation through formation amide
+Amines PG
1. Tert-butyl carbamates (BOC)
n Formation:

n Cleavage: Strong acid (3M HCl), CF3COOH


+Amines PG
2. Allyl carbamates (AllOC)
n Formation:

n Cleavage: Pd(0), Et3SiH


+Amines PG
3. Benzyl carbamates (CBz)
n Formation:

n Cleavage: Hydrogenolysis, PdCl2, Et3SiH, BBr3


+Amines PG
4. Amides

The most common,


the easiest to remove

trifluoroacetamides

Cleavage: NaOH
+Amines PG
5. Alkyl protecting group
n Formation:

BnBr

n Cleavage: H2, Pd/C, HCl


+Amines PG
6. sulfonamides
n Formation:

n Cleavage: Removal (typically very hard with


destroying substrates); Li/NH3
+ Examples 1:
n Amino group can be protected by being converted to amide.
+Amides PG

Cleavage:

PBMCl =P-methoxybenzyl chloride


CAN = ceric ammonium nitrate = strong oxidant
+
Exercise 1
+
Exercise 2
Exercise 3
+ ?

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