In the synthesis design of a molecule with several functional groups, it is very common that a reagent that produces a transformation on a functional group also affects another group present in another part of the molecule. In cases where adequate chemoselectivity cannot be achieved on the functional group to be transformed, the group that must remain unchanged is protected by temporarily converting it to functionality inert to the reaction conditions.

The protection operation requires the following procedure:

·          Protect the most reactive functional group(s) selectively and under mild conditions.

·          Carry out the reaction on the required functional group without affecting the protected group

·          Unprotect functional group, subjected to protection

The   protection action must satisfy the following basic requirements:

·          The reaction must perform well and be chemoselective.

·          The new functional group must be stable under the reaction conditions of the group that will react.

·          The introduced functionality must not add chiral centers to the molecule that can generate diasteromers

·          The original functional group must be able to be regenerated with good yield and without affecting the rest of the molecule.

The use of protectors should be reduced to the essential minimum and their choice should be such that they do not need to be replaced throughout the synthesis, since the introduction and removal steps (deprotection) add cost and work to the synthesis and decrease the yield.   Example.


The ketonic group of the molecule has been protected by transforming it into a cyclic ketal, with an ethanediol in a slightly acid medium, subsequently this molecule has been reacted with two moles of phenyl magnesium bromide, which acts on the ester group, to transform it into a tertiary alcohol, with two methyl substituents contributed by the Grignard. Finally, the cyclic ketal is hydrolyzed to regenerate the ketone.

In practice, there is no perfect protective group for each functionality, instead it can be affirmed that there is a large battery of possible protectors, each of which meets the above conditions under certain circumstances. A short list of protection of the most common groups is included in the following sections:


One way of protecting ketones and aldehydes is their conversion to acetals. Acetals can be deprotected under mild conditions by acid hydrolysis reactions.


In the reduction of a ketoester to ketoalcohol. Protection of the ketone in the form of an acetal is very convenient because the acetal resists the reducing conditions under which it will be used in the conversion of the ester group to a hydroxyl group.

The following scheme shows the complete synthesis sequence that allows achieving the reduction of the ester without affecting the ketone:


In the first stage, the ketone is converted to a cyclic acetal by reaction with ethylene glycol in the presence of an acid catalyst. In the second stage, the ester is reduced with LiAlH 4 . This reagent does not attack the acetal. Finally, in the third stage, the alcohol-acetal is treated in an aqueous acid medium. Under these conditions, the acetal is hydrolyzed, regenerating the ketonic carbonyl group. Each of the three stages is chemoselective since in each of them the preferred reaction of a functional group is achieved.   in the presence of another.


a) ethyl and methyl esters. The most common form of protection for carboxylic acids is their conversion to esters.


The most used esters are those of ethyl and methyl that can be easily obtained by means of the Fischer esterification reaction. Deprotection is carried out by acidic or basic hydrolysis (saponification) of the ester group.


b) Benzyl esters The deprotection of ethyl or methyl esters can be problematic in polyfunctional systems due to the high acidity or basicity that must be employed in the hydrolysis process. For this reason, other types of esters are used that allow the deprotection step to be carried out under neutral or low acidity conditions.


Benzyl esters can be deprotected by hydrogenolysis (broken cleavage by H 2 ) of the CO bond, at room temperature and neutral conditions.

c) t-butyl esters. t-Butyl esters can be readily hydrolyzed to the corresponding carboxylic acids, under mildly acidic conditions and room temperature, due to the easy formation of the t-butyl carbocation.



to)       Like acetals. DHP (dihydropyran) is used for the conversion of alcohols to mixed acetals. As the alcohol is converted to an acetal, deprotection is effected by acid hydrolysis.


b) As benzyl ethers. Since ethers are one of the least reactive functional groups, it is not surprising that many of them are used as protecting groups. However, the chemical inertness of ethers is a drawback when using them as protecting groups because the deprotection step requires, in many cases, the use of very drastic reaction conditions.


That is why, in practice, the number of types of ether that are used as alcohol protectors is considerably reduced. One of the most widely used ethers in the alcohol protection process is benzyl ether (ROBn). The protection stage is achieved by prior ionization of the alcohol, for example with NaH, followed by SN2 attack of the generated alkoxide on benzyl bromide or chloride.


Benzyl ethers are very popular among synthetic organic chemists because they combine great ease of introduction, great chemical inertness, and great chemoselectivity in the deprotection step. The deprotection is carried out under neutral conditions and at room temperature, by means of a hydrogenolysis reaction.

b)       As trityl ethers. Trityl ethers, or triphenyl methane ethers, are used for the chemoselective protection of primary hydroxyls. The secondary and tertiary hydroxyl groups, being more sterically hindered than the primary ones, do not form trityl ethers because triphenylmethyl chloride (trityl chloride) is a very bulky reagent.


Triphenylmethane ethers (trityl ethers) are obtained by reacting primary alcohols with trityl chloride in the presence of a non-nucleophilic tertiary nitrogenous base, such as pyridine. The mission of the base is to neutralize the HCl that is generated in the reaction. The deprotection of this type of ethers is achieved by mild acid hydrolysis. The products are two alcohols


c)        as silyl ethers. Silyl ethers are obtained by reacting alcohols with silyl chlorides. Such as triethylsilyl chloride (Et 3 SiCl), t-butyldimethylsilyl chloride (t-BuMe 2 SiCl), or t-butyldiphenylsilyl chloride (t-BuPh 2 SiCl).


The synthesis of these ethers is carried out in the presence of a non-nucleophilic base to neutralize the HCl that generates the reaction



Silyl ethers can be highly chemoselectively deprotected by reaction with salts containing the fluoride anion. This deprotection is based on the strength of the Si-F bond, one of the strongest covalent bonds that exists, which drives the reaction towards the formation of the corresponding fluorosilane.


The other product of this reaction is a salt of the alkoxide anion (RO - M + ). To obtain the alcohol, a hydrolysis stage is carried out to cause the protonation of the alkoxide anion.

The size of the three silylation reagents increases in the following order:

Et3SiCl    <     t-Bu(CH 3 ) 2 SuCl    <    t-Bu( Ph2 )SiCl

Increases the size of the silylation reagent

d) protection as esters. Alcohols can also be protected by converting them to esters.


One of the most common esters in the alcohol protection-deprotection strategy is the ester of acetic acid (acetates).


The free electronic pair located on the nitrogen atom of the amines is responsible for their nucleophilicity and basicity. The obvious way to hide the basic and nucleophilic properties of amines is their conversion into compounds in which the electron pair of nitrogen is conjugated to an electron-withdrawing group.

The conversion of amines to amides can be   a good solution for the protection of amino groups because the delocalization of the electronic density associated with the nitrogen atom decreases the basicity and nucleophilicity of this electronic pair.


This protection has a drawback: the deprotection step. Amides are not very reactive and the hydrolysis of the amide group must be carried out under conditions of high basicity (or acidity) and temperature that can affect other functional groups present in the structure. Therefore, amines are usually protected in the form of urethanes and not amides.

In urethanes the electron density of the nitrogen atom is also decreased by conjugation with a carbonyl group. The advantage of these protectants is that they can be removed under mild and highly chemoselective conditions. One of the reagents used in the protection of amines in the form of urethanes is t-butyloxycarbonyl chloride. Urethanes obtained with this reagent are abbreviated as RNHBoc


The reaction of the RNHBoc with aqueous acids, under mild conditions of acidity and temperature, generates a carbamic acid that is unstable and decarboxylates in situ.   giving rise to the free amine. Another type of urethanes used in the protection of amines are those obtained in the reaction with benzyloxycarbonyl chloride.

Amines (RNH 2 ) protected as benzyloxycarbonyl urethanes are abbreviated as RNHCBz


These urethanes are deprotected under neutral conditions by a hydrogenolysis reaction.

checkout of   N-CBz derivatives:

1st. Generation of carbamic acid by hydrogenolysis


2nd. Spontaneous decarboxylation of carbamic acid