ChemTalk

Protecting Groups in Organic Synthesis

Core Concepts

Many organic molecules have the same functional group in different spots. When chemists want to react only one of these groups, they must sometimes add a protecting group which prevents unwanted reactions to the desired functional groups.

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Protecting Group Basics

Protecting groups add to the existing functional groups to prevent them from future reaction. There are many different protecting groups based on the functional group which needs protection, and the reactions it needs protection from. However, all of these different protecting groups share some qualities.

Protecting groups add before the reaction step, and come off after, adding two steps to the synthesis for each protecting group used. Thus, it is imperative that the protecting group easily adds and removes in high yield with reagents that will not impact the rest of the molecule. Additionally, the protecting groups must target specific types or locations of the functional group which they protect, so they leave the desired functional group free to react. Additionally, the protecting groups should be different enough from the molecule to easily separate from the reaction products during workup to prevent future contaminations. Lastly, protecting groups should retain the stereochemistry of the original molecule.

How Do Protecting Groups Protect

The goal of protecting groups is to prevent reactions, but it is important to consider how they do this. There are two main ways in which protecting groups protect these areas of the molecule. This first is by adding steric bulk. By surrounding the functional groups with other atoms, it is very difficult for reactants to access this part, preventing reaction. Secondly, protecting groups can alter the chemical structure of the molecule, making it impossible to react. These normally remove some of the functionality of this functional group by taking away hydrogens, pi bonds, or other reactive structures, and tying them up in the protecting group.

Alcohol Protecting Groups

Methoxymethyl ethers (MOM)

The MOM protecting groups is one of the most versatile and widely used protecting groups for alcohols. It selectively protects primary alcohols under most conditions. The MOM protecting group is made from the reactions of the alcohol and methoxychloromethane with base as a catalyst. It comes off with a strong acid, which means that it is strong against bases, nucleophiles, and electrophiles, but not reactions involving acids.

Addition of MOM protecting group
Addition of the MOM Protecting Group

Tert-butyldimethylsilane (TBDMS)

The TBDMS group also commonly protects alcohols and sometimes amines. This protects from the reaction of the alcohol and tertiarybutyldimethylsilyl chloride (or TBDMSCl) with a base catalyst. This is a very bulky protecting group, and protects against both Sn1 and Sn2 type reactions, meaning that it can protect primary, secondary, and tertiary alcohols.

TBDMS Protecting Groups
Addition of the TBDMS Protecting Group

Tertiary-butyl (tBu)

Similar to the TBDMS group, the alcohol react to form a tertiary butyl ether protected group through a reaction with 2-methylpropene gas and an acid catalyst. This group also comes off with a strong acid, and protects in a similar way to the TBDMS group. This protection is not as commonly used as TBDMS because it can be difficult to obtain the protected molecule in high yield.

tBu ether protecting groups
Reaction of an Alcohol and 2-methylpropene to Form the Tertiary Butyl Ether

Benzyl ether (Bz)

Adding an aromatic substituent to the alcohol can have remarkable selectivity for where it adds due to electric effects elsewhere in the molecule influencing the aromaticity of the alcohol. If the alcohol is significantly aliphatic, the Williamson ether synthesis can protect the alcohol in high yield. This groups is unique because it protects against some reactions with the steric bulk of the benzene ring, but against others with the chemical aromaticity of the ring.

Benzyl Ether Protecting Group
Williamson Ether Synthesis With Bromobenzene Affords the Benzyl Ether

Amine Protecting Groups

Tertiary Butyloxycarbonyl (BOC)

Amine, like alcohols, are ubiquitous in organic molecules, and need protection against certain chemical reactions. One of the most common protecting groups for amines is the BOC group, which forms from the reaction of the amine and BOC anhydride which also forms tertiary butanol and carbon dioxide. This protecting group unfortunately degrades with strong acids, and thus cannot protect any reactions which involve acids. This protecting group takes up a lot of space, and protects through steric bulk.

BOC Protection
BOC Protection

Methylcarbamate

Another very common amine protecting group is the methyl carbamate group. The reaction between a primary amine and methylchloroformate with a Lewis base and a Bronsted base as catalysts make add this group. This group leaves the amine by hydrolysis in the presence of a concentrated strong acid and water. This group adds a protective carbonyl group right next to the amine, making many addition reactions impossible here.

Methyl Carbamate Protection of Amines
Formation of a Methyl Carbamate Protecting Group

Trifluoroacetemide

The trifluoroacetemide groups protects by adding a lot of steric bulk to a secondary amine to protect it from further reactions. To protect, the amine reacts with trifluoro acetic acid (TFAA) and a Lewis base as a catalyst. The TFA groups comes off with a much stronger acid, and protects this amine from most addition reactions, as well as most reactions involving weak acids or bases.

TFAA Protecting Groups
Addition of a TFAA Group

Tosylate

A paratoluenesulfonic acid group (commonly called a tosyl group) is one of the most common ways to protect an amine. P-toluene sulfonyl chloride is a very common reagent, that serendipitously was discovered to protect amines against redox and most electrophiles when reacted with the amine in the presence of a pyridine catalyst. P-toluene sulfonic acid and p-toluene sulfonyl chloride are catalysts for several other reactions, including some exotic esterifications, in these cases, you cannot protect an amine with this group.

Tosyl Protection
Protection of an Amine with P-Toluenesulfonyl chloride

Carbonyl Protecting Groups

Ethylene Glycol

Carbonyls can be particularly selective to reactions due to the reactive pi bond, which can often delocalize. In order to remove this reactive capability, a new group with no new pi ponds is necessary. This is achievable by reacting the carbonyl with ethylene glycol in the presence of an acid, which forms a dioxolane ring and water. This reaction occurs in equilibrium, so, in order to achieve high yeilds, the water can be removed (in accordance with Le Chatelier’s principle) to get more product.

Protection of Ketones and Aldehydes as dioxolane
Rearrangement of a Ketone Into a Dioxolane with Ethylene Glycol

Dimethylacetals

Acetals and ketals are very stable against nucleophilic attack and can easily be added with the addition of methanol and an acid catalyst. Like above, this also creates water, which can be removed to drive the reaction towards completion.

Protection of ketone with dimethlketals
Protection as a Dimethylketal

Other Protecting Groups

Carboxylic acids can be protected as Ethers

Carboxylic acids can undergo many different kinds of reactions, but are fortunately very easy to protect. These groups are most commonly protected through a Fisher Esterification, which replaces the reactive hydrogen atom with a carbon-containing group. This also produces water, which can be removed to drive the reaction forward.

Fisher esterification
Fisher Esterification