10.8

Protection of Alcohols

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Organic compounds often contain more than one functional group. In such molecules, a protecting group makes the more reactive group inert to a given set of conditions.

An analogous illustration is a pipe with multiple openings. A liquid would flow out through the lowest outlet because of gravity. However, using a cap to block the lower outlet allows the liquid to be obtained from the higher outlet.

For instance, organolithium alkylation of a halide in the presence of alcohol does not occur due to the acidity of the hydroxyl group. However, protecting the alcohol allows the alkylation of the halide.

While designing a protecting group, the fundamental principle is its stability to one set of conditions and susceptibility to another. For instance, the tetrahydropyranyl group is a common protecting group for alcohols from strong bases. While the acetal formed is stable in such conditions, it is susceptible to acid hydrolysis.

After the intended reaction, easy removal of the cap without damaging the pipe is also necessary to return the system to its native state. This process of removing the protecting group is known as deprotection.

Popular protecting groups for alcohols from nucleophiles or carbon and nitrogen bases include the trialkylsilyl family. Here, a trialkylsilyl derivative interacts with the alcohol in the presence of a weak base like imidazole that reacts as a nucleophilic catalyst to generate a trialkylsilyl ether.

These trialkylsilyl groups are then removed from alcohols using fluoride salts that are soluble in organic solvents, like tetra-n-butylammonium fluoride, or TBAF. Consequently, the re-protonation of the oxygen regenerates the native alcohol.

In addition to the reaction conditions, the reactivity of the molecule to be protected must be considered when identifying a suitable protecting group.

For instance, among alcohols, methyl ethers are suitable protecting groups only for phenols because phenoxides are good leaving groups under the deprotection conditions, while alkoxides are poor leaving groups under these conditions.

Overview

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This lesson delves into the concept of protection and deprotection of a functional group fundamental to synthetic organic chemistry. These phenomena are explained in the context of aliphatic and aromatic alcohols.

Protection

It defines a protecting group as the masking agent to make the more reactive species inert to a given set of conditions. This concept is depicted via the illustration of liquid flow through different outlets in an assembly of pipes. The analogy helps to understand the role of a protecting group in reaction selectivity, as in the case of the organolithium alkylation of a halide in the presence of a competing acidic alcohol group. The example shows how protection of the alcohol group helps to achieve the alkylation of the halide. Popular protecting groups for alcohols include the trialkylsilyl family for nucleophiles or carbon and nitrogen bases and the tetrahydropyranyl (THP) group for strong bases. In the former example, the halide of the trialkylsilyl derivative reacts with the alcohol in the presence of a nucleophilic catalyst to generate a trialkylsilyl ether.

Deprotection

Every protection is followed by deprotection after the intended reaction. The deprotection restores the system to its native state. In protection with trialkylsilyl groups, deprotection is achieved using fluoride salts like tetra-n-butylammonium fluoride (TBAF) that are soluble in organic solvents. Here, the re-protonation of the oxygen regenerates the native alcohol. In the case of protection with THP, deprotection is achieved using acid hydrolysis.

Principle of design

The lesson also elucidates the principles behind the design of a protecting group using an illustration of a house under varying external weather conditions. It demonstrates the selectivity offered by a protecting group in a specific environment. For instance, THP protects alcohol from strong bases. The acetal formed in this case is stable towards bases but susceptible to acid hydrolysis.

Apart from the reaction conditions, the reactivity of the molecule to be protected also plays a key role in designing a suitable protecting group. For example, methyl ethers’ ability to protect phenols is found inappropriate for aliphatic alcohols. Here, the stability of the corresponding leaving groups during deprotection plays a key role. For example, the alkoxides, unlike phenoxides, are poor leaving groups for deprotection with hydrogen bromide.

The following table summarizes the various protection/deprotection groups for different types of alcohols and related conditions:

Protecting group	Structure	Protects	From	Protection	Deprotection
Trialkylsilyl (R₃Si–), e.g., TBDMS	Me₃Si–OR (Me₃C)Me₂Si–OR	Alcohols (OH in general)	Nucleophiles, C or N bases	R₃SiCl, base	H⁺, H₂O, or F⁻
Tetrahydropyranyl (THP)		Alcohols (OH in general)	Strong bases	3,4-Dihydropyran, H⁺	H⁺, H₂O
Benzyl ether (OBn)		Alcohols (OH in general)	Almost everything	NaH, BnBr	H₂, Pd/C, or HBr
Methyl ether (ArOMe)		Phenols (ArOH)	Bases	NaH, MeI, or (MeO)₂SO₂	BBr₃, HBr, HI, Me₃SiI

Transcript

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Organic compounds often contain more than one functional group. In such molecules, a protecting group makes the more reactive group inert to a given set of conditions.

An analogous illustration is a pipe with multiple openings. A liquid would flow out through the lowest outlet because of gravity. However, using a cap to block the lower outlet allows the liquid to be obtained from the higher outlet.

For instance, organolithium alkylation of a halide in the presence of alcohol does not occur due to the acidity of the hydroxyl group. However, protecting the alcohol allows the alkylation of the halide.

While designing a protecting group, the fundamental principle is its stability to one set of conditions and susceptibility to another. For instance, the tetrahydropyranyl group is a common protecting group for alcohols from strong bases. While the acetal formed is stable in such conditions, it is susceptible to acid hydrolysis.

After the intended reaction, easy removal of the cap without damaging the pipe is also necessary to return the system to its native state. This process of removing the protecting group is known as deprotection.

Popular protecting groups for alcohols from nucleophiles or carbon and nitrogen bases include the trialkylsilyl family. Here, a trialkylsilyl derivative interacts with the alcohol in the presence of a weak base like imidazole that reacts as a nucleophilic catalyst to generate a trialkylsilyl ether.

These trialkylsilyl groups are then removed from alcohols using fluoride salts that are soluble in organic solvents, like tetra-n-butylammonium fluoride, or TBAF. Consequently, the re-protonation of the oxygen regenerates the native alcohol.

In addition to the reaction conditions, the reactivity of the molecule to be protected must be considered when identifying a suitable protecting group.

For instance, among alcohols, methyl ethers are suitable protecting groups only for phenols because phenoxides are good leaving groups under the deprotection conditions, while alkoxides are poor leaving groups under these conditions.

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