IV (Advance Organic Synthesis and Supramolecular Chemistry and Carbocyclic Rings) Module No and 9: Protection and Deprotection Title Module Tag CHE P14 M9

Subject Chemistry

Paper No and Title 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No and 9: Protection and deprotection Title Module Tag CHE_P14_M9

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Table of Content

1. Learning outcomes 2. Introduction 3. Protecting groups for carbonyl compounds 4. Protecting groups for alcohols 5. Protecting groups for amines 6. Summary

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

1. Learning Outcomes

After studying this module, you shall be able to  Know about protecting groups.  Study the characteristics of protecting groups.  Understand the functional group protection.  Know the protection of important functional groups.

2. Introduction

Protection and deprotection is an important part of organic synthesis. During the course of synthesis, we many times desire to perform reaction at only one of the two functional groups in any single organic molecules. For example, in an organic compound possessing two functional groups like ester and ketone, we have to perform reaction at only ester group, them the keto group needs to be protected. If we want to reduce the ester group, then keto group will also get reduced. To avoid this type of complications, protection and deprotection of functional groups are necessary.

3. Protecting groups for carbonyl compounds

The protecting groups allow the masking of a particular functional group where a specified reaction is not to be performed. The protection is required as it interferes with another reaction. Let us take the example of reduction of the keto-ester 1 to the alcohol 2 with a

nucleophilic reagent such as NaBH4 that attacks only the more electrophilic ketone. In order to make alcohol 3 by the reduction of ester, it is important to protect the ketone as an acetal 4

that allows the reduction of the ester with the more nucleophilic LiAIH4 (Figure 1).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Figure 1

In another example, 3-oxocyclohexanecarboxylic acid methyl ester (6) undergoes reduction

with lithium aluminium hydride (LiAlH4) to 3-hydroxymethylcyclohexanol (7). If we want to go for selective reduction, then the role of protection and deprotection comes.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Figure 2

During the protection, ketone from the compound 3-oxocyclohexanecarboxylic acid methyl

ester (6) forms ketals on reaction with methanol (CH3OH) under acidic conditions. The protection reaction can be reversed by treatment with water under acidic conditions (Figure 3).

Figure 3

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

The characteristics of protecting group are as follows:

1. It must be easy to put in

2. It must be resistant to reagents that would attack the unprotected function group.

3. It must be easily removed

4. Protecting groups for alcohols

Methyl ethers and simple amides are easy to synthesize and are quite resistant to variety of

reagents. From below reaction, we can see that reaction takes place to turn R1 in 13 into R2 in 16. But the protection is not very helpful as extreme conditions are required to remove them. These can be used when the molecule is stable enough to bear deprotection condition (Figure 4).

Figure 4

The Achilles Heel Strategy The Achilles Heel for the functional group ether is the use of tetrahydropyryl group (THP group). This converts ether into an acetal. The compound used to give THP derivative is dihydropyran, DHP 24. The protonation of 24 yield the compound with positive charge on oxygen 25. This is further reacted with alcohol (ROH) to give the acetal 26 (Figure 5). The

compound 2-methoxytetrahydropyran (when R = CH3) is known as the ‘the THP derivative’. For deprotection of alcohol from the protecting group, hydrolysis only requires the weak aqueous acid.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Figure 5

There is another way to make an ether easier to eliminate is to convert it into benzylic form as given in figure 6. The alcohol can be protected as benzylic ether and easily deprotected to give the desired product. For example, the alcohol 27 on reaction with benzyl chloride in the presence of base like sodium hydride (NaH) gives the alcohol protected as benzylic ether 28. We can do any reaction on the protected alcohol group and deprotection will be done by simple hydrogenation in the presence of catalyst.

Figure 6

Other popular method to protect the alcohol group is to convert them to trimethylsilyl ether. This can be done by treating the alcohol with chlorotrimethylsilane and a tertiary amine.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

5. Protecting groups for amines

Amines are the compounds that exist as R-NH2. They are further classified as primary, secondary and tertiary amines based on the number of substitution at the nitrogen atom. In all the cases, nitrogen possesses an unshared pair of electrons that causes the problem in a synthesis. This requires protection. The amines are mainly protected as amides and carbamates.

The conversion of amine to amide decreases the activity of the amino group. Amine (17) can easily be converted to corresponding amide (18) form by using acetyl chloride as shown in figure 7. The formed amide or we can say protected amine undergoes desired reaction to get converted to 19. The deprotection of 19 can easily be done with sodium hydroxide to get the free amine group 20.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Figure 7

Another example is the bromination of aniline. On brominating aniline (21) the 2,4,6- tribromo derivative (22) is formed. As we can see the yield is quantitative, but we want mono brominated product and for that excessive bromination need to be stopped. To overcome the

excess bromination, the protection of NH2- group is essential. The acetylation of aniline converts aniline to acetylaniline (23). The amide 23 on bromination gives only in the para

position (the N-acetyl group is larger than NH2) and the hydrolysis does not destroy the benzene ring (Figure 8).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

Figure 8

Other protecting group include carbamate. This is also an amide bond but with some other functionality attached that allows them to be removed under mild reaction condition in comparison to simple amide group. For example, the reaction of primary amine with tertiary- butyl chloroformate forms a carbamate under basic condition (Figure 9).

Figure 9

The protected amine can undergo any reaction and further deprotected to give the desired product.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection

6. Summary

 Protection and deprotection is an important part of organic synthesis.  Protecting groups allows masking the distinctive chemistry of a functional group as it interferes with another reaction.  The characteristics of protecting group are as follows: (i) It must be easy to put in (ii) It must be resistant to reagents that would attack the unprotected function group. (iii) It must be easily removed  Ethers and Amides are used as protecting groups when the molecule is stable enough to bear deprotection condition.  Alcohols are usually protected as ethers where as amines are protected as amide and carbamates.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 9: Protection and deprotection