Protecting Groups

ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)

UNIT- III: Protecting groups

 Protecting Groups - Protecting groups are used in synthesis to temporarily mask the characteristic chemistry of a functional group because it interferes with another reaction. - A good protecting group should be easy to put on, easy to remove and in high yielding reactions, and inert to the conditions of the reaction required. - For example:

- The overall transformation required is ester to primary alcohol. This is a reduction of the ester, which requires LiAlH4, but that will reduce the ketone as well which we don't want. We can avoid this problem if we "change" the ketone to a different functional group first. Conceptually, this is like being able to put a cover (shown below) over the ketone while we do the reduction, then removes the cover.

- In reality, the "molecular cover" is a protecting group. In this example, we protect the ketone as an acetal (which is an ether and doesn't react with LiAlH4)

- Then we can reduce the ester to the primary alcohol.

- Finally we can remove the protecting group:

- Overall, this gives us the complete scheme:

Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University

E-mail: [email protected]; [email protected]

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 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.

Note, however, that each protecting group incorporated in a multistep synthesis increases the synthesis by two non-productive steps reducing the overall yield and efficiency of the synthesis.

 Qualities of a Good Protecting Group - A good protecting group should be such that: (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.



Some Common Protecting Groups in Organic Synthesis Protection of alcohols

Protecting Groups Acetyl Benzoyl Benzyl

Removed by acid or base acid or base Hydrogenolysis

Protection of amines Protecting Groups Removed by Carbobenzyloxy (Cbz) hydrogenolysis p-Methoxybenzyl carbonyl (Moz or MeOZ) hydrogenolysis, more labile than Cbz tert-Butyloxycarbonyl (BOC) Concentrated, strong acid. (such as HCl or CF3COOH) Benzyl (Bn) group hydrogenolysis Carbamate group acid and mild heating Protection of carbonyl groups Protecting Groups Removed by Acetals and Ketals Acid hydrolysis Acylals Lewis acids Protection of carboxylic acids Protecting Groups Removed by Methyl esters acid or base Benzyl esters hydrogenolysis tert-Butyl esters Acid, base and some reductants. Silyl esters acid, base and organometallic reagents Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University


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 Protecting Groups for Alcohols - The common protecting groups for alcohols are ether-protecting groups. Ethers are among the least reactive of the organic functional groups.

- The ether protecting groups of alcohols can be grouped in the following categories: (a) Silyl ether protecting groups

(b) Acetal protecting groups

- These protections replace the acidic proton on an alcohol with an unreactive ether moiety.

(a) Protecting Groups for Alcohols (Silyl Protecting Groups)



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(b) Protecting Groups for Alcohols (Benzyl ether Protecting Groups) - Rarely are alkyl ethers used as protecting groups for alcohols, but benzyl ethers are special.

(c) Protecting Groups for Alcohols (Cyclic Acetal Protecting Groups) - Acetonide Protecting Groups for 1,2-Diols



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 Protecting Groups for Aldehydes and Ketones (Acetal and Ketal Protecting Groups)

 Synthetic Applications of the Acetal Protecting Group -

The Wieland-Miescher ketone is a common intermediate in the synthesis of both natural and synthetic steroids.

-

Because of resonance stabilization, the carbonyl of the ,-unsaturated ketone is less electrophilic and therefore less reactive to nucleophiles compared to an isolated ketone.



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 Protecting Groups for Carboxylic Acids (Esters)



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 Protecting Groups for Amino Groups (Carbamate Protecting Groups)



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Protecting Groups

Protecting Groups

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