A protecting group or protective group is introduced into a molecule by chemical modification of a
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
to obtain
chemoselectivity in a subsequent chemical reaction. It plays an important role in
multistep organic synthesis.
In many preparations of delicate
organic compounds, some specific parts of their molecules cannot survive the required reagents or chemical environments. Then, these parts, or groups, must be protected. For example,
lithium aluminium hydride
Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula Li Al H4. It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic ...
is a highly reactive but useful reagent capable of reducing
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
s to
alcohols. It will always react with
carbonyl groups, and this cannot be discouraged by any means. When a reduction of an ester is required in the presence of a carbonyl, the attack of the hydride on the carbonyl has to be prevented. For example, the carbonyl is converted into an
acetal, which does not react with hydrides. The acetal is then called a protecting group for the carbonyl. After the step involving the hydride is complete, the acetal is removed (by reacting it with an aqueous acid), giving back the original carbonyl. This step is called deprotection.
Protecting groups are more commonly used in small-scale laboratory work and initial development than in industrial production processes because their use adds additional steps and material costs to the process. However, the availability of a cheap chiral building block can overcome these additional costs (e.g.
shikimic acid for
oseltamivir).
Common protecting groups
Alcohol protecting groups
Protection of
alcohols
In chemistry, an alcohol is a type of organic compound that carries at least one hydroxyl () functional group bound to a saturated carbon atom. The term ''alcohol'' originally referred to the primary alcohol ethanol (ethyl alcohol), which is ...
:
:
*
Acetyl
In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
(Ac) – Removed by acid or base (see
Acetoxy group).
*
Benzoyl
In organic chemistry, benzoyl (, ) is the functional group with the formula C6H5CO-. It can be viewed as benzaldehyde missing one hydrogen.
The term "benzoyl" should not be confused with benzyl, which has the formula C6H5CH2. The benzoyl group ...
(Bz) – Removed by acid or base, more stable than Ac group.
*
Benzyl (Bn) – Removed by
hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry.
*
Methoxyethoxymethyl ether (MEM) – Removed by acid.
*
Dimethoxytrityl,
is-(4-methoxyphenyl)phenylmethyl(DMT) – Removed by weak acid. DMT group is widely used for protection of 5'-hydroxy group in nucleosides, particularly in
oligonucleotide synthesis
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...
.
*
Methoxymethyl ether In organic chemistry, a methoxymethyl ether is a functional group with the formula , abbreviated MOM. Methoxymethyl ethers are often employed in organic synthesis to protect alcohols. They are usually derived from 2-methoxymethyl chloride. Clo ...
(MOM) – Removed by acid.
* Methoxytrityl
4-methoxyphenyl)diphenylmethyl(MMT) – Removed by acid and hydrogenolysis.
*
''p''-Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation - commonly with
DDQ .
* ''p''-Methoxyphenyl ether (PMP) – Removed by oxidation.
*
Methylthiomethyl ether
In organic chemistry a methylthiomethyl (MTM) ether is a protective group for hydroxyl groups. Hydroxyl groups are present in many chemical compounds and they must be protected during oxidation, acylation, halogenation, dehydration and other re ...
– Removed by acid.
*
Pivaloyl
Pivalic acid is a carboxylic acid with a molecular formula of (CH3)3CCO2H. This colourless, odiferous organic compound is solid at room temperature. A common abbreviation for the pivalyl or pivaloyl group (''t''-BuC(O)) is Piv and for pivalic aci ...
(Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
*
Tert-butyl ethers (tBu) - Removed by acid.
*
Tetrahydropyranyl
Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addi ...
(THP) – Removed by acid.
*
Tetrahydrofuran
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
(THF) – Removed by acid.
*
Trityl (triphenylmethyl, Tr) – Removed by acid and hydrogenolysis.
*
Silyl ether (most popular ones include
trimethylsilyl
A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom minus;Si(CH3)3 which is in turn bonded to the rest of a molecule. This structural group is ch ...
(TMS), ''tert''-butyldimethylsilyl (TBDMS or TBS), tri-''iso''-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or
fluoride ion. (such as NaF, TBAF (
tetra-''n''-butylammonium fluoride, HF-Py, or HF-NEt
3)). TBDMS and TOM groups are used for protection of 2'-hydroxy function in nucleosides, particularly in
oligonucleotide synthesis
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...
.
* Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr
3 in DCM
* Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N
hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid. It is a component of the gastric acid in the dige ...
Amine protecting groups
Protection of
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
s:
*
Carbobenzyloxy (Cbz) group – Removed by
hydrogenolysis
*
''p''-Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by
hydrogenolysis, more labile than Cbz
*
''tert''-Butyloxycarbonyl (BOC) group (common in
solid phase peptide synthesis) – Removed by concentrated strong acid (such as HCl or CF
3COOH), or by heating to >80 °C.
* 9-Fluorenylmethyloxycarbonyl (
Fmoc) group (Common in
solid phase peptide synthesis) – Removed by base, such as
piperidine
*
Acetyl
In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
(Ac) group is common in
oligonucleotide synthesis
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...
for protection of N4 in
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
and N6 in
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
or
methylamine
Methylamine is an organic compound with a formula of . This colorless gas is a derivative of ammonia, but with one hydrogen atom being replaced by a methyl group. It is the simplest primary amine.
Methylamine is sold as a solution in methanol, ...
. Ac is too stable to be readily removed from aliphatic amides.
*
Benzoyl
In organic chemistry, benzoyl (, ) is the functional group with the formula C6H5CO-. It can be viewed as benzaldehyde missing one hydrogen.
The term "benzoyl" should not be confused with benzyl, which has the formula C6H5CH2. The benzoyl group ...
(Bz) group is common in
oligonucleotide synthesis
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...
for protection of N4 in
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
and N6 in
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or methylamine. Bz is too stable to be readily removed from aliphatic amides.
*
Benzyl (Bn) group – Removed by
hydrogenolysis
*
Carbamate group – Removed by acid and mild heating.
*
''p''-Methoxybenzyl (PMB) – Removed by
hydrogenolysis, more labile than benzyl
*
3,4-Dimethoxybenzyl (DMPM) – Removed by
hydrogenolysis, more labile than ''p''-methoxybenzyl
*
''p''-Methoxyphenyl (PMP) group – Removed by
ammonium cerium(IV) nitrate
Ceric ammonium nitrate (CAN) is the inorganic compound with the formula . This orange-red, water-soluble cerium salt is a specialised oxidizing agent in organic synthesis and a standard oxidant in quantitative analysis.
Preparation, properties, ...
(CAN)
*
Tosyl
In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a tolyl group, –, joined to a sulfonyl group, ––, with the open valence o ...
(Ts) group – Removed by concentrated acid (HBr, H
2SO
4) & strong reducing agents (
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
in liquid
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
or
sodium naphthalenide)
*
Troc (trichloroethyl chloroformate ) group – Removed by Zn insertion in the presence of acetic acid
*
Other Sulfonamides (Nosyl & Nps) groups – Removed by
samarium iodide,
thiophenol
Thiophenol is an organosulfur compound with the formula C6H5SH, sometimes abbreviated as PhSH. This foul-smelling colorless liquid is the simplest aromatic thiol. The chemical structures of thiophenol and its derivatives are analogous to phen ...
or other soft thiol nucleophiles, or
tributyltin hydride
Carbonyl protecting groups
Protection of
carbonyl groups:
*
Acetals and
Ketals – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.
*
Acylals – Removed by
Lewis acids.
*
Dithianes – Removed by metal salts or oxidizing agents.
Carboxylic acid protecting groups
Protection of
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
s:
*
Methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
esters – Removed by acid or base.
*
Benzyl esters – Removed by hydrogenolysis.
*
''tert''-Butyl esters – Removed by acid, base and some reductants.
* Esters of 2,6-disubstituted phenols (e.g.
2,6-dimethylphenol,
2,6-diisopropylphenol,
2,6-di-''tert''-butylphenol) – Removed at room temperature by
DBU
The decibel (symbol: dB) is a relative unit of measurement equal to one tenth of a bel (B). It expresses the ratio of two values of a power or root-power quantity on a logarithmic scale. Two signals whose levels differ by one decibel have a po ...
-catalyzed methanolysis under high-pressure conditions.
*
Silyl esters – Removed by acid, base and
organometallic reagents.
*
Orthoesters
In organic chemistry, an ortho ester is a functional group containing three alkoxy groups attached to one carbon atom, i.e. with the general formula . Orthoesters may be considered as products of exhaustive alkylation of unstable orthocarboxylic ...
– Removed by mild aqueous acid to form ester, which is removed according to ester properties.
*
Oxazoline
Oxazoline is a five-membered heterocyclic organic compound with the formula . It is the parent of a family of compounds called oxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are th ...
– Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100 °C), but not e.g.
LiAlH4,
organolithium reagents or
Grignard (organomagnesium) reagents
Phosphate protecting groups
* 2-cyanoethyl – removed by mild base. The group is widely used in
oligonucleotide synthesis
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...
.
*
Methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
(Me) – removed by strong nucleophiles ''e.c''. thiophenole/TEA.
Terminal alkyne protecting groups
*
Propargyl
In organic chemistry, the propargyl group is a functional group of 2- propynyl with the structure . It is an alkyl group derived from propyne ().
The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framewor ...
alcohols in the
Favorskii reaction,
* Silyl groups, especially in protection of the
acetylene
Acetylene ( systematic name: ethyne) is the chemical compound with the formula and structure . It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in its pure ...
itself.
Other
*
Photolabile protecting groups
Orthogonal protection
Orthogonal protection is a strategy allowing the specific deprotection of one protective group in a multiply-protected structure without affecting the others. For example, the amino acid
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
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 (Fmoc) by bases (such as piperidine), and the phenolic ''tert''-butyl ether cleaved with acids (e.g. with trifluoroacetic acid).
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 with regard to 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.
The technique was introduced in the field of
peptide synthesis by
Robert Bruce Merrifield in 1977. As a
proof of concept orthogonal deprotection is demonstrated in a
photochemical transesterification by
trimethylsilyldiazomethane utilizing the
kinetic isotope effect
In physical organic chemistry, a kinetic isotope effect (KIE) is the change in the reaction rate of a chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes. Formally, it is the ratio of rate constants for ...
:
:
Due to this effect the
quantum yield for deprotection of the right-side ester group is reduced and it stays intact. Significantly by placing the deuterium atoms next to the left-side ester group or by changing the wavelength to 254 nm the other monoarene is obtained.
Criticism
The use of protective groups is pervasive but not without criticism. In practical terms their use adds two steps (protection-deprotection sequence) to a synthesis, either or both of which can dramatically lower
chemical yield
In chemistry, yield, also referred to as reaction yield, is a measure of the quantity of moles of a product formed in relation to the reactant consumed, obtained in a chemical reaction, usually expressed as a percentage. Yield is one of the pr ...
. Crucially, added complexity impedes the use of synthetic total synthesis in
drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...
. In contrast
biomimetic synthesis does not employ protective groups. As an alternative, Baran presented a novel protective-group free synthesis of the compound hapalindole U. The previously published synthesis
[''Synthetic studies of marine alkaloids hapalindoles. Part 3 Total synthesis of (±)-hapalindoles H and U'' ]Tetrahedron
In geometry, a tetrahedron (plural: tetrahedra or tetrahedrons), also known as a triangular pyramid, is a polyhedron composed of four triangular faces, six straight edges, and four vertex corners. The tetrahedron is the simplest of all ...
, Volume 46, Issue 18, 1990, Pages 6351–6360 Hideaki Muratake, Harumi Kumagami and Mitsutaka Natsume according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):
Industrial applications
Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g.:
*
Oseltamivir (Tamiflu, an antiviral drug) synthesis by
Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...
*
Sucralose
Sucralose is an artificial sweetener and sugar substitute. The majority of ingested sucralose is not broken down by the body, so it is noncaloric. In the European Union, it is also known under the E number E955. It is produced by chlorination ...
(sweetener)
References
External links
Introduction of protecting group and mechanism of deprotectionSenior undergraduate study notes on this subject, from Prof. Rizzo. A further set of study notes in tutorial form, with guidance and comments, from Profs. Grossman and Cammers. A review by Prof. Kocienski. A user site excerpting the classic Greene and Wuts text regarding stability of a few key groups, from this reference's extensive tables.
{{DEFAULTSORT:Protecting Group
Chemical synthesis