Unit - 3 Part - B of Advanced Organic Chemistry - I (MPC 102T), M. Pharm. (Pharm. Chem.), AKTU Lucknow.

1. by : Rajnish Kumar, Assistant Professor & Ajay Kumar, M.
Pharma Student, Noida Institute of Engineering &
Technology, Pharmacy Institute, Plot no. 19, Knowledge
Park-2, Institutional Area, Greater Noida, U. P., India-
201306.
PROTECTING GROUPS IN ORGANIC CHEMISTRY

2. Role of protection in
organic chemistry

3. • a.When there are two functional groups of unequal reactivity within a
molecule, the more reactive group can be made to react alone, but it may
not be possible to react the less reactive functional group selectively.
b. A group the use of which makes possible to react a less reactive
functional group selectively in presence of a more reactive group is known
as protecting group.
c. A protecting group blocks the reactivity of a functional group by
converting it into a different group which is inert to the conditions of some
reaction(s) that is to be carried out as part of a synthetic route.
d. When we choosing a suitable protecting group, the following features
must be considered.
Cheap and commercially available
Simple to put in high yield
Stable to reaction conditions
Easy to remove in high yield

4. ◦ Protection of Alcohols.
◦ Protection of Carbonyl Groups in Aldehyde And Ketones.
◦ Protection of Carboxylic acid.
◦ Protection of amines.
Protecting groups for
different functional groups

5. Protection of Alcohols

6. By putting a bulky protecting group on the hydroxyl oxygen
which can sterically prevent it from competing effectively
for electrophiles.
Principle of protection of alcohols

7. Bydelocalising the lone pairs of electrons by conjugation

8. Acetals Or Ketals As Protecting Groups For Alcohols
Ether As Protecting Groups For Alcohals
Ester As Protecting Groups For Alcohals
Protecting groups for alcohols

9. Acetals or ketals as protecting
groups for alcohol

10. Acelals or ketals not only serve as useful protecting groups for
aldehydes and ketones but they also find widespread use in the
protection of alcohols.
Commonly used ketals include Tetrahydropyranyl (THP)
derivatives, methoxyethoxymethyl (MEM) derivative and
methoxymethyl (MOM) derivative.
Acetals / ketals are simply removed by treatment with
aqueous acid.

13. Ether as protecting groups for
alcohols

14. Alcohols may be simply converted to ethers by
nucleophilic attack on a suitable alkyl halide.
Ethers are stable to basic and mildly acidic
conditions; they do not react with oxidizing /
reducing agents and are inert to organo-metallic
reagents. However, this stability means that many
others are not easily cleaved to their parent
alcohol under mild conditions. Therefore, only
certain ethers, which are easily cleaved under
mild conditions, are commonly used as protecting
groups for alcohols.

15. Benzyl ether which are converted to alcohols
under neutral conditions by catalytic
hydrogenolysis.
For example:-

16. t-butyl ethers which are readily hydrolyzed with dilute
acid.

17. Tri-phenylmethyl group is the most important
for the protection of 1°-alcoholic group. Only 1°-
alcohols react at a useful rate with trityl-chloride in
pyridine so selective protection of primary hydroxyl
groups is possible.

18. Trimethylsilyl ethers as protecting groups

19. Esters As Protecting Group For
Alcohol

21. Trichloroacetate esters
[Cl3CCOOR]:
Pivoloate ester
[Me3CCOOR]:-

22. Protection of 1,2 & 1,3 diols

23. Cis 1, 2 diols and cis and trans-1,3 diols can be
protected as cyclic acetals and ketals (e.g., dioxlanes
and dioxanes) or cylic ortho esters that are cleaved by
acidic hydrolysis or as cylic esters (e.g, carbonates) that
are cleaved by basic hydrolysis.
Cyclic ortho esters are more readily cleaved by acidc
hydrolysis than cyclic acetals or ketals.

24. Isopropylidene (acetonides):-
1, 2 acetanoid formation is usually favored
over 1, 3 acetonidess
Cleavage:-mild aqueous acid
Cyclic acetals and krtals

29. Protection of carbonyl groups
in aldehyde and ketones

30. The acetal / ketals protective group is introduced by treating
the carbonyl compounds with an alcohol, an ortho-ester, or
a diol in the presence of a Lewis acid as catalyst.
Acetals / ketals are stable to strong aqueous bases,
nucleophilic reducing agents, organometallic reagents,
oxidation under non-acidic conditions, Na or Li/NH3
reductions.
Acetals / ketals are cleaved by acid-catalyzed hydrolysis
Acetal / ketals as protecting group

31. General order of reactivity of various carbonyl
groups (probably due to the steric effect).
1,3-dioxanes (six-membered ring) hydrolyze faster than the
corres-ponding 1,3-dioxolanes (five- membered ring acetal)

32. Acyclic acetals is prepared by the reaction of aldehyde with
monohydric alcohal in the presence of dry HCl.
Preparation of acyclic ketals and acetals

33. Acylic ketones cannot be prepared with monohydric
alcohols under the same condition of acetals formation
because of the unfavourable entropy, which the equillbrium
towards the ketones So acyclic ketals are prepared by the
reaction of ketones with ethylorthoformate in presence of
the NH4Cl.

34. Preparation of cyclic acetal & ketals

35. Thioacetals / thioketals are quite stable toward hydrolysis;
there is no special need to remove the H2O formed during
the reaction.
Thioacetal/ Thioketals as protecting group

38. Protection of the Carboxyl Group
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.
Most common group for the protection of
acid is ester.

46. Protection of Amines
The basic problem of peptide synthesis is one of
protecting the amino group. In bringing about
interaction between the carboxyl group of one amino
acid and the amino group of a different amino acid, one
must prevent interaction between the carboxyl group
and the amino group of the same amino acid. In
preparing glycylalanine, for example, one must prevent
the simultaneous formation of glycylglycine. Reaction
can be forced to take place in the desired way by
attaching to one amino acid a group that renders the
NH2 unreactive.

47. Protecting Groups for Amines (RNH2,
RNHR’, RNR’ R”) groups :-

50. 1.Singh, J ; Yadav, L.D.S; Organic Synthesis;Pragati Publicaton; thirteenth edition-
2017; pp. 696- 721.
2.Kar, K.R.; Application of Redox and Reagents in Organic Synthesis; New
Central Book Agency (P) Ltd; volume-1; pp 376-385.
3.Clayden, J; Greeves, N; Warren, S; Wothers, P;
Organic Chemistry; pp 633-637 & 657
4.Hanson, J.R.; Protecting Groups in Organic Synthesis; Sheffield Academic
Press; pp 8- 80.
5.Morrison, R.T.; Boyd R.N.; Organic Chemistry; Prentice-Hall of India Private
Limited; Sixth Edition- 2002; pp. 1147
6.March, J; Smith, M.B.; March’sAdvanced Organic Chemistry: Reactions,
Mechanisms, and Structure; Wiley Publication; Sixth Edition; pp 1271-1279
References :-

51. Thank you!