2. Protection of carbonyl and carboxyl group
Submitted to Ms. Arifa
Submitted by Khadija Nasir
Roll number 1922107019
BS. Chemistry
Semester 7
Government Graduate College for Women, Gulberg, Lahore
3. Content
• Protecting group
• Carbonyl protecting group
Protection by alcohol
Protection by diol
Protection by thiol and dithiol
Protection by hemiacetal formation
• Carboxyl group protection
t-butyl ester formation
Silyl ester formation
Benzyl and phenyl ester formation
Ethyl ester formation
• Past paper’s questions
• References
5. Protecting groups
• A protecting group or protective group is a group that is introduced
into a molecule by chemical modification of a functional group to
obtain chemo selectivity in a subsequent chemical reaction
LiAlH4
• It can be used in a poly functional molecule to block the reactivity of
selective functional group under reaction condition
• Order of reactivity is as follows
Alcohol > amine > aldehyde > ketone > carboxylic acid
6. Properties
• Easy to introduce
• It should leave easily
• It should be cheaply available
• It should not react with other components in a reaction
• After introduction of protecting group asymmetric carbon
should not generate
• Every functional group has specific protecting groups
PG LiAlH4
7. Protection of carbonyl group
• Carbonyl group is present in aldehyde and ketone
• Carbonyl group is highly reactive because it acts as both
electrophile and nucleophile
• Aldehyde is more reactive than ketone
• Protecting groups for carbonyl are alcohol, diol, thiol, dithiol,
hemiacetal in the presence of acid
• Semicarbazides, cyanohydrins, imines, hydrazones can
protect carbonyl group but its de protection is difficult
8. • Decreasing order of reactivity of carbonyl compounds is as follows
Aliphatic aldehyde > aromatic aldehyde > acyclic ketones >
cyclohexanones > cyclopentanone > alpha beta unsaturated ketone > >
aromatic ketone
• Following compounds are generally formed while using
protecting groups
1. Acyclic acetal or ketal
2. Cyclic acetal or ketal
3. Dithio acetal or ketal
4. Hemithio acetal or ketal
2CH3OH
2CH3OH
Aldehyde Acetal Acetone Ketal
9. 1. Acyclic acetal and ketal
• It is formed by using alcohol in the presence of acid
• This protecting group is good for aldehyde not for ketones specially
dimethyl ketone.
2 ROH
H+
ROH
Dry HCl
Acetaldehyde methyl acetal
Mechanism
10. - H2O ROH
- H+
+
H+
Trimethyl ortho formate
• Other reagent can be trimethyl ortho formate
Acetaldehyde
12. H2O
- ROH - H+
2. Cyclic acetal and ketal
• This is better due to entropic advantage because aliphatic acetal formation includes (1
carbonyl group and 2 alcoholic group) while it includes (1 carbonyl and 1 diol)
• It is acid catalyzed reaction of carbonyl and 1,3 diol or 1,2 diol
• Solvents can be dry HCl or TsOH, acetone
17. <
• Reactivity order for ketal
• Reactivity order for acetal
>
1,3 dioxane
1,3 dioxalane
1,3 dioxalane 1,3 dioxane
• Ketal will cleave more easily than acetal
18. Selective protection of carbonyls
• Aldehydes can be selectively protected in the presence of
ketone
• When both ketone or both aldehyde are present the
selectively less hindered ketone will be protected
H+
H+
19. • Conjugated carbonyl will be protected slower than saturated
carbonyl
3. Dithio acetal and ketal
• Carbonyl group can be protected by sulphur derivative
+
BF3.Et2O / CHCl3
− H2O
Dithio ketal
20. +
Cleavage
• Acid catalyzed cleavage is not satisfactory
• Cleavage can be done in 2 ways
i. Using Hg+2 salt like HgCl2, HgClO4 in the presence of
BF3.Et2O complex as a solvent
BF3.Et2O, Hg(ClO4) + 2
21. I2 / NaHCO3, HCl
II. Cleavage through oxidation
Following oxidizing agents can be used
• I2 / NaHCO3, HCl
• H2O2, BF3.Et2O, HCl
• NaIO4, BF3.Et2O, HCl
• O2, BF3.Et2O, HCl
Note
This protection is not suitable if the reaction is occurring in basic
condition because thio acetal and ketal are sensitive toward
base
+2
24. Cleavage
Cleavage can be done by using Hg+2 salt or oxidizing agents
Following oxidizing agents can be used
• I2 / DMSO aq. MeOH
• BF3.Et2O, H2O2, CH2Cl2
CH2Cl2 / BF3.Et2O, HgCl2
or
I2 / DMSO aq. MeOH
or
BF3.Et2O, H2O2, CH2Cl2
+
27. Reason of dominance of thio acetal and ketal
• Sulphur derivatives selectively protect aldehyde in the
presence of ketone
• It protects alpha beta unsaturated carbonyl group without
migration of double bond
• 1,3 dioxolane or 1,3 dioxane is readily converted into1,3
dithiolane or 1,3 dithiane
30. Protection of carboxyl group
• Protection of carboxyl group is done by converting it to ester
• Following esters could be formed
Methyl and ethyl ester ( less used due to difficulty in
deprotection)
Silyl ester
t-butyl ester
Benzyl ester
Phenyl ester
37. Question 1 (2016)
Give two method for the protection of carbonyl and hydroxyl group?
Answer
Carbonyl group can be protected by
1.Acyclic acetal and ketal formation
2.Cyclic acetal and ketal formation
3.Acyclic and cyclic thio acetal and ketal formation
4.Hemiacetal and hemiketal formation
Past paper
38. Question 2 (2018)
Give the protection of following functional group present in following compound?
i. OHCH2CH2CHCHO
ii. CH3COCH2CH2COOH
iii. CH2COCH2CH2CH2CHO
Alcohol > amine > aldehyde > ketone >
carboxylic acid
iii. CH2COCH2CH2CH2CHO
i. OHCH2CH2CHCHO
ii. CH3COCH2CH2COOH
Answer