Protection of Alcohols

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