Name: alcohol protecting groups in synthesis
Uploaded: 2023-04-30T18:28:39.000Z
Duration: 2 min 31 s
Channel: JoVE

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 nucleophi

protection of alcohols

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.
<h4>Protection</h4>
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.
<h4>Deprotection</h4>
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.
<h4>Principle of design</h4>
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&#8217; 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:
<table style="margin-left: auto; margin-right: auto;">
	<tbody style="border: 1px solid black;">
		<tr>
			<td style="color: black; border: 1px solid black; text-align: center;">Protecting group</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Structure</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Protects</td>
			<td style="color: black; border: 1px solid black; text-align: center;">From</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Protection</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Deprotection</td>
		</tr>
		<tr>
			<td style="color: black; border: 1px solid black; text-align: center;">Trialkylsilyl (R3Si&#8211;), 
			e.g., TBDMS</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Me3Si&#8211;OR 
			(Me3C)Me2Si&#8211;OR</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Alcohols 
			(OH in general)</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Nucleophiles, 
			C or N bases</td>
			<td style="color: black; border: 1px solid black; text-align: center;">R3SiCl, 
			base</td>
			<td style="color: black; border: 1px solid black; text-align: center;">H+, H2O, 
			or F&#8722;</td>
		</tr>
		<tr>
			<td style="color: black; border: 1px solid black; text-align: center;">Tetrahydropyranyl 
			(THP)</td>
			<td style="color: black; border: 1px solid black; text-align: center;"><img alt="Cyclic acetal structure; organic chemistry formula; diagram for chemical synthesis study." src="/files/ftp_upload/11927/Figure_1-11927.svg" style="text-align: center; height: 50px;" data-altupdatedat="1761830439000" data-alt="Figure1" /></td>
			<td style="color: black; border: 1px solid black; text-align: center;">Alcohols 
			(OH in general)</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Strong bases</td>
			<td style="color: black; border: 1px solid black; text-align: center;">3,4-Dihydropyran, 
			H+</td>
			<td style="color: black; border: 1px solid black; text-align: center;">H+, H2O</td>
		</tr>
		<tr>
			<td style="color: black; border: 1px solid black; text-align: center;">Benzyl ether 
			(OBn)</td>
			<td style="color: black; border: 1px solid black; text-align: center;"><img alt="Aromatic ether structure with RO group, chemical diagram for organic chemistry study." src="/files/ftp_upload/11927/Figure_2-11927.svg" style="text-align: center; height: 50px;" data-altupdatedat="1761830439000" data-alt="Figure2" /></td>
			<td style="color: black; border: 1px solid black; text-align: center;">Alcohols 
			(OH in general)</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Almost everything</td>
			<td style="color: black; border: 1px solid black; text-align: center;">NaH, BnBr</td>
			<td style="color: black; border: 1px solid black; text-align: center;">H2, Pd/C, 
			or HBr</td>
		</tr>
		<tr>
			<td style="color: black; border: 1px solid black; text-align: center;">Methyl ether 
			(ArOMe)</td>
			<td style="color: black; border: 1px solid black; text-align: center;"><img alt="Methoxyphenyl chemical structure with variable R group; organic chemistry diagram." src="/files/ftp_upload/11927/Figure_3-11927.svg" style="text-align: center; height: 50px;" data-altupdatedat="1761830439000" data-alt="Figure3" /></td>
			<td style="color: black; border: 1px solid black; text-align: center;">Phenols 
			(ArOH)</td>
			<td style="color: black; border: 1px solid black; text-align: center;">Bases</td>
			<td style="color: black; border: 1px solid black; text-align: center;">NaH, MeI, or 
			(MeO)2SO2</td>
			<td style="color: black; border: 1px solid black; text-align: center;">BBr3, HBr, HI, 
			Me3SiI</td>
		</tr>
	</tbody>
</table>

This lesson delves into the concept of protection and deprotection of a functional group fundamental to synthetic organic chemistry. These phenomena are ...

Education

JoVE Core

Organic Chemistry

Unit 1

Alcohols and Phenols

KEY TERMS AND CONCEPTS

alcohol protecting groups in synthesis

Alcohol protecting groups help control which part of an organic molecule reacts during synthesis. A protecting group is a masking agent that makes a more reactive species inert under a chosen set of conditions. The lesson uses a pipe-flow analogy to show how this improves reaction selectivity. It also shows how protecting an alcohol can allow an organolithium alkylation of a halide to occur when the alcohol would otherwise compete.

Common protecting groups for alcohols include trialkylsilyl groups and tetrahydropyranyl, or THP, groups. Trialkylsilyl groups are useful when the reaction mixture contains nucleophiles or carbon and nitrogen bases. They are formed when the alcohol reacts with a trialkylsilyl halide in the presence of a nucleophilic catalyst to give a trialkylsilyl ether. THP protection is often used when strong bases are present.

Deprotection removes the masking group after the target reaction is complete. This step restores the molecule to its native alcohol form. Trialkylsilyl groups are removed with fluoride salts such as tetra-n-butylammonium fluoride, or TBAF, which is soluble in organic solvents. During this step, the oxygen is re-protonated to regenerate the alcohol. THP groups are removed by acid hydrolysis.

The design of a protecting group depends on the reaction conditions and on the molecule being protected. The lesson compares this idea to a house exposed to different weather conditions. THP protection forms an acetal that is stable toward bases but sensitive to acid hydrolysis, so it works well against strong bases. The choice also depends on how the leaving group behaves during deprotection. For example, methyl ethers can protect phenols, but they are not suitable for aliphatic alcohols because alkoxides are poor leaving groups compared with phenoxides.

The lesson also summarizes several protection and deprotection systems. Trialkylsilyl groups such as TBDMS protect alcohols from nucleophiles and carbon or nitrogen bases, and they are removed with H+, H2O, or F−. THP protects alcohols from strong bases and is removed with H+, H2O. Benzyl ethers protect alcohols from almost everything and are installed with NaH and BnBr, then removed with H2 and Pd/C or with HBr. Methyl ethers protect phenols from bases and are removed with BBr3, HBr, HI, or Me3SiI.

Alcohol Protecting Groups in Synthesis

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Learn how alcohol protecting groups control reaction selectivity, including trialkylsilyl, THP, benzyl ether, and methyl ether protection and deprotection.

Alcohol Protecting Groups in Synthesis | JoVE K12

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Alcohol Protecting Groups in Synthesis

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