Protection for the carbonyl group

1. PROTECTION FOR THE CARBONYL
GROUP &CARBOXYL GROUP
PRESENTED BY- INDRAJIT SAMANTA
M.PHARM ( PHARMACEUTICAL CHEMISTRY), 1ST SEM, 1ST YEAR
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
SPER, JAMIA HAMDARD, NEW DELHI

2. LIST OF CONTENTS
INTRODUCTION
PROTECTING GROUPS FOR CARBOXYLIC
ACIDS
PROTECTION FOR CARBONYL GROUP –
ACETYL & KETAL
REFERENCES

3. INTRODUCTION
CHEMO SELECTIVITY
Which functional groups will
react
REGIO SELECTIVITY
Where it will react

4. INTRODUCTION
 Which functional group reacts first 1. Reaction
2. Condition
3. reagents

5. INTRODUCTION
 WHAT IS A PROTECTING GROUP?
A protecting group (PG) is a molecular framework that is introduced onto a specific functional group (FG) in a
poly-functional molecule to block its reactivity under reaction conditions needed to make modifications
elsewhere in the molecule.
R-FG PG R-FG-PG
Free functional group (reactive) MUSK FUNCTIONAL GROUP(
Unreactive)

6. QUALITIES OF A GOOD PROTECTING GROUP IN ORGANIC
SYNTHESIS
 (a) It should be readily, but selectively introduced to the desired functional group in a poly-
functional molecule.
 (b) It should be stable / resistant to the reagents employed in subsequent reaction steps in
which the group being masked (protected) is desired to remain deactivated (protected).
 (c) It should be capable of being selectively removed under mild conditions when its
protection is no longer required
TACTICAL CONSIDERATIONS
Easy & efficient
introduction
stable throughout
reaction, work up &
purification
efficient and
selective removal
under mild
conditions
should not create any
stereo-genic centre

7. PROTECTING GROUPS FOR CARBOXYLIC ACIDS
Protecting groups for carboxylic acids are used to avoid reaction of the acidic -COOH hydrogen with bases and
nucleophiles or to prevent nucleophilic additions at the carbonyl carbon.
Esters:
The common ester protecting groups for carboxylic acids are methyl, ethyl and benzyl esters.
METHYL ESTER (RCOOCH3)
Formation:
1. RECTION WITH CH2N2

8.  2. REACTION WITH CH3OH IN ACID MEDIA:
RCOOH + CH3OH RCOOCH3
H+ ( - H2O)
3) RECTION WITH CH3OH IN ISOCYNIDE:
RCOOH + MeOH RNC RCOOMe
CLEAVAGE:
1 RCOOMe + Mg3SiCl NaI, MeCN RCOOH
2. RCOOCH3 + BBr3 CH2Cl2 RCOOH
3. RCOOCH3 + LiCl DMF RCOOH

9. CARBOXYLIC ESTER
Ethyl and benzyl esters are prepared based on the following rationale:
Best approach:

10. MECHANISM OF DCC COUPLING

11. ETHYL ESTERS
 FORMATION:
 CLEAVAGE:

12. BENZYL ESTERS
 FORMATION:
 CLEAVAGE:

13. TERT-BUTYLOXY-CARBONYL PROTECTING GROUP (BOC)

14. TERT- BUTYLOXY CARBONYL PROTECTING GROUP (BOC)

15. AMIDES
 Amide condensation of phenylacetic acid and benzylamine with various catalysts under sealed conditions
 FORMATION
 Direct amide condensation of various carboxylic acids and amines by 8a ( SiO2

17. PROTECTION FOR CARBONYL GROUP – ACETYL & KETAL
INTRODUCTION:
 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.
 Semi-carbazides, cyanohydrins, imines, hydrazones can protect carbonyl group but its de protection is difficult

18. PROTECTION FOR CARBONYL GROUP – ACETYL & KETAL
 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

19. CARBONYL
PROTECTION
Acid catalysed
Acid catalysed Cyclic acetal
Diol
alcohol
Aliphatic acetal
thiol hemithiol
Aliphatic thio acetal Hemithi acetal oxidation
Hg2+ or oxidation

20. ACYCLIC ACETAL AND KETAL
 Acyclic acetal and ketal is formed by using alcohol in the presence of acid.
 This protecting group is good for aldehyde not for ketones specially dimethyl ketone.
 Mechanism:

21. ACYCLIC ACETAL AND KETAL
 Other reagent can be trimethyl ortho formate
 Cleavage:

22. ACYCLIC ACETAL AND KETAL
 Mechanism:

23. 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 HCI or TsOH, acetone.
 Formation:

24. Mechanism:
Advantage:
 Cyclic acetals and ketals do not react with base, Grignard reagent and reducing agents like LiAlH4

25. CYCLIC ACETAL AND KETAL
 Cleavage

26. REACTIVITY ORDER FOR CYCLIC ACETAL/ KETAL
 Ketal will cleave more easily than acetal
 Reactivity order for ketal
 Reactivity order for acetal

27. 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
 Conjugated carbonyl will be protected slower than saturated carbonyl

28. DITHIO ACETAL AND KETAL
 Carbonyl group can be protected by sulphur derivative
 Cleavage
 Acid catalyzed cleavage is not satisfactory Cleavage can be done in 2 ways Using Hg2+ salt like HgCl2, HgCIO
in the presence of BF3, Et2O complex as a solvent

29. DITHIO ACETAL AND KETAL
Cleavage through oxidation
Following oxidizing agents can be used
 This protection is not suitable if the reaction is occurring in basic condition because thio acetal and ketal are sensitive
toward base.

30. CYCLIC DITHIO ACETAL AND KETAL
 Formation:
 Mechanism:

31. CYCLIC DITHIO ACETAL AND KETAL
 Cleavage
 It can be done by using Hg2+ salt or oxidizing agents.
 Following oxidizing agents can be used

32. Mechanism of cleavage by help of HgCl2:

33. Mechanism of oxidative cleavage :

34. HEMI-THIO ACETAL & KETAL
 Formation:
 Cleavage:

35. REFERENCES:
 [02:57, 27/12/2022] Is: https://profiles.uonbi.ac.ke/andakala/files/sch_5
04_protecting_groups_in_organic_synthesis.
 pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC 6859800/
 https://www.organic chemistry.org/protective groups/carbonyl.shtm
 Singh, J; Yadav, L.D.S; Organic Synthesis;Pragati Publicaton; thirteenth edition-2017; pp. 696- 721.