PROTECTING GROUPS (PROTECTION FOR THE CARBOXYLIC GROUP & PROTECTION FOR THE AMINO GROUP

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3. What are protecting groups ?
 A protecting group is introduced into a molecule by chemical
modification of a functional group to obtain chemo selectivity in
a chemical reaction.
 It plays an important role in multistep organic synthesis
 When a chemical reaction is to be carried out selectively at one
reactive site in a multifunctional compound, other reactive sites
must be temporarily blocked.
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4. Overall transformation required is ester to primary alcohol.
In reduction of the ester, which requires LiAlH4, but it will reduce the ketone.
We can avoid this problem if we "change" the ketone to a different functional group first.
This is like being able to put a cover (shown below) over the ketone while we do the reduction, then remove the
cover
The "molecular cover" is a protecting group. we protect the ketone as an acetal(which is an ether and doesn't
react with LiAlH4)
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5. Finally we can remove the protecting group
Then we can reduce the ester to the primary alcohol.
OVERALL SCHEME
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6. Qualities of a Good Protecting Group in
Organic Synthesis
 It must react selectively in good yield to give a protected substrate that
is stable to the projected reactions.
 The protective group must be selectively removed in good yield by
readily available, preferably nontoxic reagents that do not attack the
regenerated functional group.
 The protective group should form a derivative (without the generation
of new stereogenic centers) that can easily be separated from side
products associated with its formation or cleavage.
 The protective group should have a minimum of additional
functionality to avoid further sites of reaction.
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7. PROTECTING GROUPS IN ORGANIC SYNTHESIS
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8. PROTECTION FOR CARBOXYLIC GROUP

9.  The protecting groups typically used for carboxylic acids are ester-
based with the methyl ester
 Regeneration of the carboxylic acid is usually achieved by
saponification or other hydrolytic methods, although non-basic
reagents, such as lithium halides, are used.
 Alternatively, more specialist esters may be used in cases where the
methyl ester or its deprotection protocol is unsuitable.
 These includes tert-butylesters, deprotected by acid/heat ,
 Trimethylsilylethyl esters, de-protected with tetra-n-butylammonium
fluoride (TBAF),
 3-propionitrile (2-cyanoethyl) esters, deprotected by mild base.
PROTECTION FOR CARBOXYLIC GROUP 9

10. Why a Carboxylic Acid group be protected?
 To mask the acidic proton so that it does not interfere with base -catalysed
reactions
 To prevent nucleophilic addition reactions
 To improve the handling of the molecule
Example-
 To make the compound less water soluble ,
 To improve its NMR characteristics
 To make it more volatile so that it can be analysed by gas
chromatography.
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11. Carboxylic acid protecting groups
Methyl ester
Benzyl ester
tert-Butyl ester
Oxazoline
Silyl ester
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12.  For example, lithium aluminium hydride is a highly reactive but useful
reagent capable of reducing esters to alcohols.
 The carbonyl is converted into an acetal which does not react with
hydrides.
 The acetal is then called a protecting group for the carbonyl group
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16. PROTECTION FOR THE AMINO GROUP

17. PROTECTION FOR AMINO GROUP
 Amino groups easily undergoes reactions with oxidizing reagents,
alkylating reagents, and many carbonyl compounds.
 In order to prevent the amino group from undergoing such reactions
it must be suitably protected.
 Many methods are available for protecting amino groups .
 It is due to peptide synthesis has become very important .
 It is not possible to build a peptide of specific structure from its
component amino acids unless the amino groups can be suitably
protected.
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19. A) PROTONATION
B) ALKYLATION
C) ACYLATION
D) SULFONYLATION
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20. A) PROTONATION
 Reactivity of amines is due to the bond which is made with unshared
electron pair on nitrogen.
 This reduces the reactivity of this electron pair & reduces the reactivity of the
nitrogen atom.
 The simplest way is to convert the amine to an ammonium salt with an acid.
 Protonation amounts to protection of the amine function:
 Unless the acid concentration is very high, there will be a significant
proportion of unprotected free base present.
 Also, many desirable reactions are not feasible in acid solution.
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21. B) ALKYLATION
 An alkylation is suitable for primary and secondary amines:
 At first glance, you may not consider that such reactions achieve protection
because there is an electron pair on nitrogen in the products.
 However, it a suitably bulky alkylating agent, RX, is used the reactivity of the
resulting alkylated amine can be reduced considerably by a steric effect.
 The most useful group of this type is the triphenylmethyl group (C6H5)3C−,
which can be introduced on the amine nitrogen by the reaction of triphenyl
methyl chloride ("trityl"chloride) with the amine in the presence of a suitable
base to remove the HCl that is formed:
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22.  The triphenyl methyl group can be removed from the amine nitrogen under
very mild conditions, either by catalytic hydrogenation or by hydrolysis in
the presence of a weak acid:
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23. C) ACYLATION
One useful way of reducing the basicity and nucleophilicity of an amine
nitrogen is to convert it to an amide by treatment with an acid chloride or acid
anhydride
The reduced reactivity is associated with the stabilization produced by the
attached carbonyl group because of its ability to accept electrons from the
nitrogen atom. This can be seen clearly in valence-bond structures 9a and 9b,
which show electron delocalization of the unshared pair of the amide function:
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24.  The stabilization energy (SE) of a simple amide grouping is about 18kcal mol−1
and if a reaction occurs in which the amide nitrogen acts as an electron-pair donor,
almost all of the electron delocalization of the amide group is lost in the transition
state
 This loss in stabilization energy at the transition state makes an amide far less nucleophilic than
an amine.
 The most common acylating agents are the acyl chlorides and acid anhydrides of ethanoic acid
and benzoic acid.
 The amine can be recovered from the amide by acid- or base-catalyzed hydrolysis:
 Another useful protecting group for amines has the structure R−O−CO−.
 It differs from the common acyl groups of the type R−CO− in that it has
the alkoxycarbonyl structure rather than an alkylcarbonyl structure.
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25. The most used examples are:
 The phenylmethoxycarbonyl (benzyloxycarbonyl) group can be introduced by
way of the corresponding acyl chloride, which is prepared from
phenylmethanol (benzyl alcohol) and carbonyl dichloride:
 The tert-butoxycarbonyl group cannot be introduced by way of the
corresponding acyl chloride because (CH3)3COCOCl is unstable.
 One of several alternative derivatives is the azide, ROCON3:
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26. Although these protecting groups may seem bizarre, their value lies in the
fact that they can be removed easily by acid-catalyzed hydrolysis under very
mild conditions.
The sequence of steps is shown in Equation 23-10 and involves proton
transfer to the carbonyl oxygen and cleavage of the carbon-oxygen bond by
an SN1 process (R= tert-butyl) or SN2 process (R= phenylmethyl).
 The product of this step is a carbamic acid.
Acids of this type are unstable and readily eliminate carbon dioxide, leaving
only the free amine
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27. D)SULFONYLATI
ONA sulfonyl group, RSO2−, like an acyl group, R−CO− or RO−CO−, will
deactivate an attached nitrogen.
Therefore amines can be protected by transformation to sulfonamides with
sulfonyl chlorides
 However, sulfonamides are much more difficult to hydrolyze back to the
amine than are carboxamides.
 In peptide synthesis the commonly used sulfonyl protecting groups are 4-
methylbenzenesulfonyl or 4-bromobenzenesulfonyl groups.
 These groups can be removed as necessary from the sulfonamide by
reduction with sodium metal in liquid ammonia.
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28. REFERENCE
 John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic
Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-
8053-8329-8.
 Protection of Carboxyl Groups E. Haslam Department of Chemz"stry,
University of Sheffield, Sheffield, England
 Protective groups in organic synthesis, third edition, theodora.W.Greene,Peter
G.M. Wuts
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