Protecting group

What is a protecting group?

A protecting group is a derivative that blocks a certain functional group from interfering at some stage of a chemical reaction in the synthesis process of a compound. The most commonly used protecting groups in organic synthesis are the protection of alcohol groups (-OH) and carbonyl groups (>C=O).

Examples of protecting groups

Protection of alcohols

Table 1: Frequent protective groups (alcohols)
Group

{Type}

Protection \

Deprotection

Stable /

Incompatible

Acetate

(AcO)

CH3COO-R

{ester}

CH3COCl / pyridine

CH3COOH / H3O+

acid or basic hydrolysis

electrophiles, oxidizing agents, mild acidic and/or basic media, NaBH/ strong acids, bases and organometallic nucleophiles, LiAlH4

Benzyl

(BnOR)

Ph-CH2-OR

{ether}

C6H5-CH2-Br / NaH

hydrogenation

oxidants, bases, nucleophiles, reductants /

strong acid,

H2 /cat, Na/NH3

Trityl

(TrO-)

(Ph)3C-OR

{ether}

(C6H5)3C-Cl / pyridine

acid medium

bases / acids

TESO-

{silyl ether}

(Et)3Si-Cl / base

F or H3O+

oxidants, nucleophiles / acidsa

TBDMSO-

{silyl ether}

t-Bu(CH3)2Si-Cl / base \

F or H3O+

oxidants, nucleophiles / acidsa

TIPSO-

{silyl ether}

(is-Pr)3Si-Cl / base

F or H3O+

oxidants, nucleophiles / acidsa

TMSO-

{silyl ether}

(Me)3Si-Cl / base \

F or H3O+

oxidants, nucleophiles / acidsa

Protection of diols

1,2-diols and 1,3-diols can be protected in the form of acetals (cyclic or acyclic). The most common are isopropylidene derivatives (acetonides) and another possibility are benzylidene derivatives.

The acetonides will be formed with the corresponding diol plus acetone. An acid catalyst is needed for the reaction to take place, usually para-toluensulfonic acid (PTSA or TsOH).

 

For the reaction to proceed correctly, water must be removed from the medium.

JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluensulfonic acid PTSA TsOH
JOXIMZWYDAKGHI-UHFFFAOYSA-N

Another possibility in which benzaldehyde in acid medium (acid catalysis) is used instead of acetone is shown in the following scheme:

example protecting group 1,2-diol benzaldehyde benzaldehyde benliciden

In both cases, the subsequent deprotection step is carried out in aqueous acidic medium. Benzylidene derivatives can also be deprotected by hydrogenolysis (H2/Pd).

The acetonides preferably form 5-membered rings while the benzylidene derivatives preferably form 6-membered rings.

For example, the following scheme shows the preference of acetonides to form 5-membered rings.

example protecting group 1,3-diol acetonides

On the other hand, this other example illustrates the preference of benzylidene derivatives to form 6-membered rings.

example 1,3-diol benzylidene protecting group

The most frequent protective groups of 1,2-diols and 1,3-diols are summarized below:

Table 2: Frequent protecting groups (1,2- and 1,3-diols)
Group

{Type}

Protection \

Deprotection

Stable /

Incompatible

{acetal}

Benzaldehyde /

mineral acid or Lewis acid.

\ hydrogenolysis or acid hydrolysis, I/ acetone

Bases, nucleophiles, oxidants, reductants acid medium, halogens, H2 / cat.

{acetal}

Acetone / acid

acid hydrolysis

I2 / acetone

Bases, nucleophiles, oxidants, reductants / acid medium

Protection of aldehydes and ketones

The carbonyl groups (aldehydes and ketones) will be protected when a nucleophile or reducing agent is used. In this way we prevent the carbonyl group from reacting.

  • Formación de cetales o acetales: se suelen formal acetales cíclicos y el reactivo que se utiliza es el etilenglicol en presencia de ácido.

example protecting group ethylene glycol cyclic acetals

Al igual que en el caso de los glicoles, la desprotección se lleva a cabo en medio ácido acuoso (H2O/H+).

  • Formation of 1,3-oxathiolanes: in this case we use 2-hydroxy-1-ethanethiol (HS-CH2-CH2OH) in the presence of boron trifluoride, BF3 ( Lewis acid) as a reagent.

example protecting group 2-hydroxy-1-ethanethiol thioacetonides

In this case the deprotection is achieved with Raney Nickel which is a reductant.

  • Formation of dithioacetals: in this case, we will use the HS-CH2-CH2SH dithiol in the presence of a Lewis acid.

example dithiol protecting group dithioacetals

The deprotection is carried out in aqueous medium in the presence of a Cl+, NO+, or Cu2+ source that activates the deprotection. As can be seen, deprotection of these groups can be carried out selectively.

In Table 3, the most common protecting groups of aldehydes and ketones are summarized.

Table 3: Frequent protecting groups (aldehydes and ketones)
Group

{Type}

Protection \

Deprotection

Stable /

Incompatible

RCH(OR’)2

{cyclic or acyclic acetal}

R’OH / H+ acid hydrolysis

bases, nucleophiles, reductants /

electrophiles, acids

RCH(SR’)2

{cyclic or acyclic thioacetal}

R’SH / mineral acid or Lewis acid mercuric salts

nucleophilic bases, electrophiles (except MeI)

oxidants, H2/cat, halogens, peracids, MeI

Protection of amines

Amines are nucleophiles and on the other hand hydrogen has a weakly acidic character and therefore will react with bases.

If either of these two features interfere with the synthetic sequence, the amine must be protected (secondary, R2NH, or primary, RNH2).

There are several possibilities for their protection:

  • Formation of carbamates or amides:

The most frequently obtained carbamates are t-butylcarbamate (BOC) or benzylcarbamate (CBz).

LFKDDJXLFVYVEFG-UHFFFAOYSA-N 
t-butyl carbamate

 

PUJDIJCNWWFYVJX-UHFFFAOYSA-N benzylcarbamate

The BOC protection reaction proceeds in a basic aqueous medium, sodium hydroxide (NaOH) or triethanolamine (Et3N) can be used, and proceeds as follows:

example carbamate protecting group t-butylpirocarbonate

On the other hand, deprotection is performed by using an acid (PTSA, CF3COOH).

If we use CBz, the protective reaction is performed as follows:

example carbamate benzylpirocarbonate protecting group

This group can be deprotected by hydrogenolysis (H2/Pd).

  • Formation of amides:

Protection of primary amines can be carried out in the form of phthalimides, using phthalic anhydride, as follows:

Deprotection is performed with hydrazine (H2N-NH2) or sodium borohydride (NaBH4) in EtOH/water.

Finally, Table 4 summarizes the most frequent protective groups of amines.

Table 4: Frequent protecting groups (amines)
Group

{Type}

Protection \

Deprotection

Stable /

Incompatible

Acetamide

AcONHR’

{amides}

Ac2O

CH3COCl / base \

hydrolysis with strong acids

Oxidant electrophiles

Bases , NaBH4,

Hydrogenation /

RLi,

LiAlH4,

LDA

t-butylcarbamate

(BocNHR)

RNHOCOt-Bu

{carbamate}

With base \

HCl 3 M o

CF3COOH

Bases, oxidant, nucleophilic reductants except RLi, RMgX /

strong acids

Protection of carboxyl groups

Protection of a carbonyl group (-COOH) can be carried out in two ways: either by protecting the -OH, or by protecting the carbonyl >C=O.

The hydroxyl (-OH) is protected in ester form, while the carbonyl (>C=O) is realized in oxazoline form, from the reagent isobutanol-2-amine.

example protecting group carboxylic acid oxazoline

Another reagent that has been used is 2,2-dimethylaziridine.

FGRJGEWVJCCOJJ-UHFFFAOYSA-N 2,2-dimethylaziridine
FGRJGEWVJCCOJJ-UHFFFAOYSA-N

Deprotection is performed in aqueous media (H+/H2O).