Protecting group


A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
In many preparations of delicate organic compounds, specific parts of the molecules cannot survive the required reagents or chemical environments. These parts must be protected. For example, lithium aluminium hydride is a highly reactive reagent that usefully reduces esters to alcohols. It always reacts with carbonyl groups, and cannot be discouraged by any means. When an ester must be reduced in the presence of a carbonyl, hydride attack on the carbonyl must be prevented. One way to do so converts the carbonyl into an acetal, which does not react with hydrides. The acetal is then called a protecting group for the carbonyl. After the hydride step is complete, aqueous acid removes the acetal, restoring the carbonyl. This step is called deprotection.
Protecting groups are more common in small-scale laboratory work and initial development than in industrial production because they add additional steps and material costs. However, compounds with repetitive functional groups – generally, biomolecules like peptides, oligosaccharides or nucleotides – may require protecting groups to order their assembly. Also, cheap chiral protecting groups may often shorten an enantioselective synthesis.
As a rule, the introduction of a protecting group is straightforward. The difficulties rather lie in their stability and selective removal. Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.

Orthogonal protection

Orthogonal protection is a strategy allowing the specific deprotection of one protective group in a multiply-protected structure. For example, the amino acid tyrosine could be protected as a benzyl ester on the carboxyl group, a fluorenylmethylenoxy carbamate on the amine group, and a tert-butyl ether on the phenol group. The benzyl ester can be removed by hydrogenolysis, the fluorenylmethylenoxy group by bases, and the phenolic tert-butyl ether cleaved with acids.
A common example for this application, the Fmoc peptide synthesis, in which peptides are grown in solution and on solid phase, is very important. The protecting groups in solid-phase synthesis regarding the reaction conditions such as reaction time, temperature and reagents can be standardized so that they are carried out by a machine, while yields of well over 99% can be achieved. Otherwise, the separation of the resulting mixture of reaction products is virtually impossible.
A further important example of orthogonal protecting groups occurs in carbohydrate chemistry. As carbohydrates or hydroxyl groups exhibit very similar reactivities, a transformation that protects or deprotects a single hydroxy group must be possible for a successful synthesis.

Cleavage categorization

Many reaction conditions have been established that will cleave protecting groups. One can roughly distinguish between the following environments:
  • Acid-labile protecting groups
  • Base-labile protecting groups
  • Fluoride-labile protecting groups
  • Enzyme-labile protecting groups
  • Reduction-labile protecting groups
  • Oxidation-labile protecting groups
  • Protecting groups cleaved by heavy metal salts or their complexes.
  • Photolabile protecting groups
  • Double-layered protecting groups
Various groups are cleaved in acid or base conditions, but the others are more unusual.
Fluoride ions form very strong bonds to silicon; thus silicon protecting groups are almost invariably removed by fluoride ions. Each type of counterion, i.e. cleavage reagent, can also selectively cleave different silicon protecting groups depending on steric hindrance. The advantage of fluoride-labile protecting groups is that no other protecting group is attacked by the cleavage conditions.
Lipases and other enzymes cleave ethers at biological pH and temperatures. Because enzymes have very high substrate specificity, the method is quite rare, but extremely attractive.
Catalytic hydrogenation removes a wide variety of benzyl groups: ethers, esters, urethanes, carbonates, etc.
Only a few protecting groups can be detached oxidatively: the methoxybenzyl ethers, which oxidize to a quinomethide. They can be removed with ceric ammonium nitrate or dichlorodicyanobenzoquinone.
Allyl compounds will isomerize to a vinyl group in the presence of noble metals. The residual enol ether or enamine hydrolyzes in light acid.
Photolabile protecting groups bear a chromophore, which is activated through radiation with an appropriate wavelength and so can be removed. For examples the o-nitrobenzylgroup ought be listed here.
The rare double-layer protecting group is a protected protecting group, which exemplify high stability.

Common protecting groups

Alcohol protecting groups

The classical protecting groups for alcohols are esters, deprotected by nucleophiles; triorganosilyl ethers, deprotected by acids and fluoride ions; and acetals, deprotected by weak acids. In rarer cases, a carbon ether might be used.
The most important esters with common protecting-group use are the acetate, benzoate, and pivalate esters, for these exhibit differential removal. Sterically hindered esters are less susceptible to nucleophilic attack:
Triorganosilyl sources have quite variable prices, and the most economical is chlorotrimethylsilane, a Direct Process byproduct. The trimethylsilyl ethers are also extremely sensitive to acid hydrolysis and are consequently rarely used nowadays as protecting groups.
Aliphatic methyl ethers cleave with difficulty and only under drastic conditions, so that these are in general only used with quinonic phenols. However, hemiacetals and acetals are much easier to cleave.

List

Esters:
  • Acetyl – Removed by acid or base.
  • Benzoyl – Removed by acid or base, more stable than Ac group.
  • Pivaloyl – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
Silyl ethers:
Benzyl ethers:
  • Benzyl — Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry.
  • Trityl — Removed by acid and hydrogenolysis
  • p-Methoxybenzyl ether — Removed by acid, hydrogenolysis, or oxidation – commonly with DDQ.
  • p,''mDimethoxybenzyl ether — Removed via oxidation with DDQ or ceric ammonium chloride
Acetals:
  • Dimethoxytrityl, — Removed by weak acid. DMT group is widely used for protection of 5'-hydroxy group in nucleosides, particularly in oligonucleotide synthesis.
  • Methoxytrityl – Removed by acid and hydrogenolysis.
  • Benzyloxymethyl — Comparable stability to MOM, MEM und SEM, but also admits reductive removal: sodium in liquid ammonia, catalytic hydrogenation, or Raney nickel in ethanol
  • Ethoxyethyl ethers – Cleavage more trivial than simple ethers e.g. 1N hydrochloric acid
  • Methoxyethoxymethyl ether — Removed by hydrobromic acid in tetrahydrofuran or zinc bromide in dichloromethane
  • Methoxymethyl ether — Removed by 6 M hydrochloric acid in tetrahydrofuran/water
  • Tetrahydropyranyl — Removed by acetic acid in tetrahydrofuran/water, p''toluenesulfonic acid in methanol
  • Methylthiomethyl ether — Removed by acid or soft metal oxidants: base-buffered mercuric chloride in wet acetonitrile or silver nitrate in wet tetrahydrofuran
  • Trissilyloxymethyl — Commonly protects 2'-hydroxy function in oligonucleotide synthesis.
  • βethoxymethyl — More labile than MEM and MOM to acid hydrolysis: 0.1 M hydrochloric acid in methanol, concentrated hydrofluoric acid in acetonitrile, boron trifluoride etherate in dichloromethane, or tetrabutylammonium fluoride in HMPT or in tetrahydrofuran
Other ethers:
  • p-Methoxyphenyl ether – Removed by oxidation.
  • Tert-butyl ethers – Removed with anhydrous trifluoroacetic acid, hydrogen bromide in acetic acid, or 4 N hydrochloric acid
  • Allyl — Removed with potassium tertbutoxide DABCO in methanol, palladium on activated carbon, or diverse platinum complexes – conjoined with acid workup.
  • Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM. See
  • Tetrahydrofuran – Removed by acid.

    1,2-Diols

The 1,2diols present for protecting-group chemistry a special class of alcohols. One can exploit the adjacency of two hydroxy groups, e.g. in sugars, in that one protects both hydroxy groups codependently as an acetal. Common in this situation are the benzylidene, isopropylidene and cyclohexylidene or cyclopentylidene acetals.
An exceptional case appears with the benzylideneprotecting group,which also admits reductive cleavage. This proceeds either through catalytic hydrogenation or with the hydride donor diisobutyl aluminum hydride. The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.