A
protecting group or
protective group is introduced into a molecule by chemical modification of a
functional groupIn organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
in order to obtain
chemoselectivityChemical reactions are defined usually in small contexts , such generalizations are a matter of utility. The preferential outcome of one instance of a generalized reaction over a set of other plausible reactions, is defined as chemoselectivity...
in a subsequent chemical reaction. It plays an important role in multistep
organic synthesisOrganic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
.
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 hydrideLithium aluminium hydride, commonly abbreviated to LAH or known as LithAl, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters,...
is a highly reactive but useful reagent capable of reducing
esterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
s to
alcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s. It will always react with
carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
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
acetalAn acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
, 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 acidShikimic acid, more commonly known as its anionic form shikimate, is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi , from which it was first isolated....
for
oseltamivirOseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
).
Alcohol protecting groups
Protection of alcohols:
- Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
(Ac) - Removed by acid or base (see Acetoxy groupAcetoxy group, abbreviated AcO or OAc, is a chemical functional group of the structure CH3-C-O-. It differs from the acetyl group CH3-C- by the presence of one additional oxygen atom...
).
- Benzoyl
In organic chemistry, benzoyl is the acyl of benzoic acid, with structure C6H5CO-. It should not be confused with benzyl, which is the radical or ion formed from the removal of one of the methyl hydrogens of toluene...
(Bz) - Removed by acid or base, more stable than Ac group.
- Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
(Bn, Bnl) - Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry.
- β-Methoxyethoxymethyl ether (MEM) - Removed by acid.
- Dimethoxytrityl, [bis-(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.
- Methoxymethyl ether (MOM) - Removed by acid.
- Methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT) - Removed by acid and hydrogenolysis.
- p-Methoxybenzyl ether (PMB) - Removed by acid, hydrogenolysis, or oxidation.
- Methylthiomethyl ether
In organic chemistry a methylthiomethyl 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 reactions to which they are susceptible.Many kinds of...
- Removed by acid.
- Pivaloyl (Piv) - Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
- Tetrahydropyranyl (THP) - Removed by acid.
- Trityl (triphenylmethyl, Tr) - Removed by acid and hydrogenolysis.
- Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
(most popular ones include trimethylsilylA trimethylsilyl group is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si3], which is in turn bonded to the rest of a molecule...
(TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) - Removed by acid or fluorideFluoride is the anion F−, the reduced form of fluorine when as an ion and when bonded to another element. Both organofluorine compounds and inorganic fluorine containing compounds are called fluorides. Fluoride, like other halides, is a monovalent ion . Its compounds often have properties that are...
ion. (such as NaF, TBAF (Tetra-n-butylammonium fluorideTetra-n-butylammonium fluoride or TBAF is a quaternary ammonium salt with the chemical formula 4N+F-. It is commercially available as the trihydrate and as a solution in tetrahydrofuran....
, HF-Py, or HF-NEt3)). TBDMS and TOM groups are used for protection of 2'-hydroxy function in nucleosides, particularly in oligonucleotide synthesisOligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure . The technique is extremely useful in current laboratory practice because it provides a rapid and inexpensive access to custom-made oligonucleotides of the desired...
.
- Methyl Ethers - Cleavage is by TMSI in DCM or MeCN or Chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM
- Ethoxyethyl ethers (EE) - Cleavage more trivial than simple ethers e.g. 1N Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
Amine protecting groups
Protection of
amineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s:
- Carbobenzyloxy
Carboxybenzyl or Cbz or Z is an amine protecting group in organic synthesis. It is commonly used in peptide synthesis and is formed by reacting an amine with benzyl chloroformate and a weak base:It is used to protect amines from electrophiles...
(Cbz) group - Removed by hydrogenolysisHydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes "lysis" by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without...
- p-Methoxybenzyl carbonyl (Moz or MeOZ) group - Removed by hydrogenolysis
Hydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes "lysis" by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without...
, more labile than Cbz
- tert-Butyloxycarbonyl
Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis. This carbonate ester reacts with amines to give N-tert-butoxycarbonyl or so-called t-BOC derivatives. These derivatives do not behave as amines, which allows certain subsequent transformations to occur that would have...
(BOC) group (Common in solid phase peptide synthesis) - Removed by concentrated, strong acid. (such as HCl or CF3COOH)
- 9-Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis) - Removed by base, such as piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
- Acetyl (Ac) group is common in oligonucleotide synthesis for protection of N4 in cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
and N6 in adenineAdenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous ammoniaAmmonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
or methylamineMethylamine is the organic compound with a formula of CH3NH2. This colourless gas is a derivative of ammonia, but with one H atom replaced by a methyl group. It is the simplest primary amine. It is sold as a solution in methanol, ethanol, THF, and water, or as the anhydrous gas in pressurized...
. Ac is too stable to be readily removed from aliphatic amides.
- Benzoyl (Bz) group is common in oligonucleotide synthesis for protection of N4 in cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
and N6 in adenineAdenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
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
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
(Bn) group - Removed by hydrogenolysisHydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes "lysis" by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without...
- Carbamate
Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
group - Removed by acid and mild heating.
- p-Methoxybenzyl (PMB) - Removed by hydrogenolysis
Hydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes "lysis" by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without...
, more labile than Benzyl
- 3,4-Dimethoxybenzyl (DMPM) - Removed by hydrogenolysis
Hydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes "lysis" by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without...
, more labile than p-methoxybenzyl
- p-methoxyphenyl (PMP) group - Removed by Ammonium cerium(IV) nitrate
Ceric ammonium nitrate is the inorganic compound with the formula 2Ce6. This orange-red, water-soluble cerium salt is widely used as an oxidising agent in organic synthesis and as a standard oxidant in quantitative analysis....
(CAN)
- Tosyl
A tosyl group is CH3C6H4SO2. This group is usually derived from the compound 4-toluenesulfonyl chloride, CH3C6H4SO2Cl, which forms esters and amides of toluenesulfonic or tosylic acid...
(Ts) group - Removed by concentrated acid (HBr, H2SO4) & strong reducing agents (sodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
in liquid ammoniaAmmonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
or sodium naphthalenideSodium naphthalenide, also known as sodium naphthalide, is a soluble one-electron reductant employed in organic, organometallic, and inorganic chemistry. It is prepared by stirring sodium metal with naphthalene in a polar solvent such as tetrahydrofuran or dimethoxyethane, resulting in the...
)
- Other Sulfonamides
A tosyl group is CH3C6H4SO2. This group is usually derived from the compound 4-toluenesulfonyl chloride, CH3C6H4SO2Cl, which forms esters and amides of toluenesulfonic or tosylic acid...
(Nosyl & Nps) groups - Removed by samarium iodide, tributyltin hydrideTributyltin hydride is an organotin compound with the formula 3SnH. It is a colorless liquid that is soluble in organic solvents. The compound is used as a source of hydrogen atoms in organic synthesis.-Synthesis and characterization:...
Carbonyl protecting groups
Protection of
carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
groups:
- Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
s and Ketals - Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.
- Acylal
Acylals in organic chemistry are a group of chemical compounds sharing a functional group with the general structure R-C2. Acylals can be obtained by reaction of aldehydes with acetic anhydride and a suitable catalyst for instance with sulfated zirconia at low temperatures when used as protective...
s - Removed by Lewis acid]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
s.
- Dithiane
A dithiane is a heterocyclic compound composed of a cyclohexane core structure wherein two methylene units are replaced by sulfur centres. The three isomeric parent heterocycles are 1,2-dithiane, 1,3-dithiane and 1,4-dithiane....
s - Removed by metal salts or oxidizing agents.
Carboxylic acid protecting groups
Protection of
carboxylic acidCarboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s:
- Methyl esters - Removed by acid or base.
- Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
esters - Removed by hydrogenolysis.
- tert-Butyl esters - Removed by acid, base and some reductants.
- Silyl esters - Removed by acid, base and organometallic reagents.
- Orthoesters - Removed by mild aqueous acid to form ester, which is removed according to ester properties.
- Oxazoline
Oxazoline is both the five-membered ring heterocyclic chemical compound with the formula C3H5NO and the class of compounds containing this ring.- See also :* Desoxazoline * Oxazole* Oxazolidine* Oxazolidinedione...
- Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100 °C), but not e.g. LiAlH4Lithium aluminium hydride, commonly abbreviated to LAH or known as LithAl, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters,...
, organolithium reagentAn organolithium reagent is an organometallic compound with a direct bond between a carbon and a lithium atom. As the electropositive nature of lithium puts most of the charge density of the bond on the carbon atom, effectively creating a carbanion, organolithium compounds are extremely powerful...
s or Grignard (organomagnesium) reagents
Phosphate protecting groups
- 2-cyanoethyl - removed by mild base. The group is widely used in oligonucleotide synthesis.
- Methyl (Me) - removed by strong nucleophiles e.c. thiophenole/TEA.
Terminal alkyne protecting groups
- propargyl
In organic chemistry, propargyl is an alkyl functional group of 2-propynyl with the structure HC≡C−CH2−, derived from the alkyne propyne.The term propargylic refers to a saturated position on a molecular framework next to an alkynyl group...
alcohols in the Favorskii reactionThe Favorskii reaction , named for the Russian chemist Alexei Yevgrafovich Favorskii, is a special case of nucleophilic attack on a carbonyl group involving a terminal alkyne with acidic protons....
,
- silyl groups, especially in protection of the acetylene
Acetylene is the chemical compound with the formula C2H2. 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 pure form and thus is usually handled as a solution.As an alkyne, acetylene is unsaturated because...
itself.
Orthogonal protection
Orthogonal protection is a strategy allowing the deprotection of multiple protective groups one at a time each with a dedicated set of reaction conditions without affecting the other. It was introduced in the field of
peptide synthesisIn organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
by
Robert Bruce MerrifieldRobert Bruce Merrifield was an American biochemist who won the Nobel Prize in Chemistry in 1984 for the invention of solid phase peptide synthesis.-Early life:...
in 1977. As a
proof of conceptA proof of concept or a proof of principle is a realization of a certain method or idea to demonstrate its feasibility, or a demonstration in principle, whose purpose is to verify that some concept or theory that has the potential of being used...
orthogonal deprotection is demonstrated in a photochemical
transesterificationIn organic chemistry, transesterification is the process of exchanging the organic group R″ of an ester with the organic group R′ of an alcohol. These reactions are often catalyzed by the addition of an acid or base catalyst...
by
trimethylsilyldiazomethaneTrimethylsilyldiazomethane, 3SiCHN2, is a diazo compound widely used as a less-explosive replacement for diazomethane.-Preparation:Trimethylsilyldiazomethane may be prepared from reacting methylmagnesium chloride with diphenyl phosphorazidate.-Uses:Trimethylsilyldiazomethane is a commercially...
utilizing the
kinetic isotope effectThe kinetic isotope effect is the ratio of reaction rates of two different isotopically labeled molecules in a chemical reaction. It is also called "isotope fractionation," although this term is somewhat broader in meaning...
:
Due to this effect the
quantum yieldThe quantum yield of a radiation-induced process is the number of times that a defined event occurs per photon absorbed by the system. The "event" may represent a chemical reaction, for example the decomposition of a reactant molecule:...
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
In a 2007 paper Phil Baran notes that even though the textbooks state that the use of protective groups is unavoidable and that they are ideally easily added and removed, in practical terms in organic synthesis their use adds two synthetic steps (protection-deprotection sequence) to a chemical sequence and sometimes dramatically lowers chemical yield. Crucially, added complexity impedes the use of synthetic total synthesis in
drug discoveryIn the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
. 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 according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):
|
|valign=top | |
| Hapalindole U Baran 2007 protective-group free |
|
Hapalindole U Muratake 1990 Ts A tosyl group is CH3C6H4SO2. This group is usually derived from the compound 4-toluenesulfonyl chloride, CH3C6H4SO2Cl, which forms esters and amides of toluenesulfonic or tosylic acid...
protective groups in blue |
Industrial applications
Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g.:
- Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
(Tamiflu, an antiviral drug) synthesis by Roche
- Sucralose
Sucralose is an artificial sweetener. The majority of ingested sucralose is not broken down by the body and therefore it is non-caloric. In the European Union, it is also known under the E number E955. Sucralose is approximately 600 times as sweet as sucrose , twice as sweet as saccharin, and 3.3...
(sweetener)
External links
For introduction of protecting group and mechanism of deprotection See : http://www.biocis.u-psud.fr/spip.php?article332