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Ethylene glycol protects a ketone (as an acetal) during an ester reduction, vs. unprotected reduction to a diol

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.^[1]

In many preparations of delicate organic compounds, specific parts of the molecules cannot survive the required reagents or chemical environments. These parts (functional groups) 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 (e.g. shikimic acid for oseltamivir).

As a rule, the introduction of a protecting group is straightforward. The difficulties honestly lie in their stability and in selective removal. Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.^[2]

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 (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.^[3] 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 (see also § Industrial applications).^[4]

Schematic diagram of a solid-state peptide synthesis with orthogonal protecting groups X and Y
Fmoc solid state peptide synthesis with orthogonal protecting groups

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:^[5]

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 (5-9) and temperatures (30–40 °C). 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 (CAN) or dichlorodicyanobenzoquinone (DDQ).

Allyl compounds will isomerize to a vinyl group in the presence of noble metals. The residual enol ether (from a protected alcohol) or enamine (resp. amine) hydrolyzes in light acid.

Photolabile protecting groups bear a chromophore, which is activated through radiation with an appropriate wavelength and so can be removed.^[6] 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 (hemi)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:

Chloroacetyl > acetyl > benzoyl > pivaloyl

Trimethylsilyl chloride, activated with imidazole, protects a secondary alcohol

Triorganosilyl sources have quite variable prices, and the most economical is chlorotrimethylsilane (TMS-Cl), a Direct Process byproduct. The trimethylsilyl ethers are also extremely sensitive to acid hydrolysis (for example silica gel suffices as a proton donator) 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.

Protection of alcohol as tetrahydropyranyl ether followed by deprotection. Both steps require acid catalysts.

List

Esters:

Acetyl (Ac) – Removed by acid or base (see Acetoxy group).
Benzoyl (Bz) – Removed by acid or base, more stable than Ac group.
Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.

Silyl ethers:

Trimethylsilyl (TMS) — Potassium fluoride, acetic acid or potassium carbonate in methanol^[7]
Triethylsilyl — 10–100× stabler than a TMS group.^[8] Cleaved with trifluoroacetic acid in water/tetrahydrofuran,^[9] acetic acid in water/tetrahydrofuran,^[10] or hydrogen fluoride in water or pyridine^[11]
tert-Butyldimethylsilyl (TBDMS or TBS) — Cleaved with acetic acid in tetrahydrofuran/water,^[12] Pyridinium tosylate in methanol,^[13] trifluoroacetic acid in water,^[14] hydrofluoric acid in acetonitrile,^[15] pyridinium fluoride in tetrahydrofuran,^[16] tetrabutylammonium fluoride in THF.^[17] Commonly protects 2'-hydroxy function in oligonucleotide synthesis.
Triisopropylsilyl (TIPS) ethers) — Similar conditions to TBS but longer reaction times.^[18]
tert‑Butyldiphenylsilyl (TBDPS) — Similar conditions to TBS but even longer reaction times (100–250× slower than TBS and 5–10× slower than TIPS)

Benzyl ethers:

Benzyl (Bn) — Removed by hydrogenolysis.^[19] Bn group is widely used in sugar and nucleoside chemistry.
Trityl (triphenylmethyl, Tr) — Removed by acid^[20]^[21]^[22] and hydrogenolysis
p-Methoxybenzyl ether (PMB) — Removed by acid, hydrogenolysis, or oxidation – commonly with DDQ.^[23]
p,m‑Dimethoxybenzyl ether — Removed via oxidation with DDQ or ceric ammonium chloride^[24]

Acetals:

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.
Methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT) – Removed by acid and hydrogenolysis.
Benzyloxymethyl — Comparable stability to MOM, MEM und SEM,^[25] but also admits reductive removal: sodium in liquid ammonia,^[26]^[27] catalytic hydrogenation (palladium hydroxide on activated carbon), or Raney nickel in ethanol^[28]^[29]
Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N hydrochloric acid^[30]
Methoxyethoxymethyl ether (MEM) — Removed by hydrobromic acid in tetrahydrofuran^[31] or zinc bromide in dichloromethane^[32]
Methoxymethyl ether (MOM) — Removed by 6 M hydrochloric acid in tetrahydrofuran/water^[33]
Tetrahydropyranyl (THP) — Removed by acetic acid in tetrahydrofuran/water,^[34] p‑toluenesulfonic acid in methanol^[35]
Methylthiomethyl ether — Removed by acid^{[citation needed]} or soft metal oxidants: base-buffered mercuric chloride in wet acetonitrile^[36] or silver nitrate in wet tetrahydrofuran^[37]
Tris(isopropyl)silyloxymethyl (TOM) — Commonly protects 2'-hydroxy function in oligonucleotide synthesis.
β‑(Trimethylsilyl)ethoxymethyl — More labile than MEM and MOM to acid hydrolysis: 0.1 M hydrochloric acid in methanol,^[38] concentrated hydrofluoric acid in acetonitrile,^[13] boron trifluoride etherate in dichloromethane,^[39] or tetrabutylammonium fluoride in HMPT (Hexamethyl phosphoric acid triamide) or in tetrahydrofuran^[40]^[41]

Other ethers:

p-Methoxyphenyl ether (PMP) – Removed by oxidation.^{[citation needed]}
Tert-butyl ethers (tBu) – Removed with anhydrous trifluoroacetic acid, hydrogen bromide in acetic acid, or 4 N hydrochloric acid^[42]
Allyl — Removed with potassium tert‑butoxide^[43] DABCO in methanol, palladium on activated carbon, or diverse platinum complexes – conjoined with acid workup.^[44]
Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr₃ in DCM
Tetrahydrofuran (THF)^{[clarification needed]} – Removed by acid.

1,2-Diols

The 1,2‑diols (glycols) 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 (DIBAL). The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.^[45]^[46]

Amine protecting groups

Amines have a special importance in peptide synthesis, but are a quite potent nucleophile and also relatively strong bases. These characteristics imply that new protecting groups for amines are always under development.^[47]

Amine groups are primarily protected through acylation, typically as a carbamate. When a carbamate deprotects, it evolves carbon dioxide. The commonest-used carbamates are the tert-butoxycarbonyl, benzoxycarbonyl, fluorenylmethylenoxycarbonyl, and allyloxycarbonyl compounds.

Other, more exotic amine protectors are the phthalimides, which admit reductive cleavage,^[48] and the trifluoroacetamides, which hydrolyze easily in base. Indoles, pyrroles und imidazoles — verily any aza-heterocycle — admit protection as N‑sulfonylamides,which are far too stable with aliphatic amines.^[49] N‑benzylated amines can be removed through catalytic hydrogenation or Birch reduction, but have a decided drawback relative to the carbamates or amides: they retain a basic nitrogen.

Selection

Carbamates:

Carbamate group – Removed by acid and mild heating.
Carbobenzyloxy (Cbz) group — Removed by hydrogenolysis: hydrogen and palladium on activated carbon,^[50] or lithium or sodium in liquid ammonia.^[51]
p-Methoxybenzyloxycarbonyl (Moz or MeOZ) group – Removed by hydrogenolysis, more labile than Cbz
tert-Butyloxycarbonyl (Boc) group — Removed by concentrated strong acid (such as HCl^[52] or CF₃COOH^[53]), or by heating to >80 °C. Common in solid phase peptide synthesis.
9-Fluorenylmethyloxycarbonyl (Fmoc) group — Removed by base, such as 20–50 % piperidine in dimethylformamide (DMF)^[54] or N-Methyl-2-pyrrolidone,^[55] or 50% morpholine in DMF for sensitive glycopeptides.^[56]^[57] Common in solid phase peptide synthesis
Allyloxycarbamate group — Removed with complexes of metals like palladium(0) or nickel(0).^[58]

Other amides:

Acetyl (Ac), Benzoyl (Bz) groups — common in oligonucleotide synthesis for protection of N⁴ in cytosine and N⁶ in adenine. Removed by base, often aqueous or gaseous ammonia or methylamine. Too stable to readily remove from aliphatic amides.
Troc (trichloroethyl chloroformate ) group – Removed by Zn insertion in the presence of acetic acid
Tosyl (Ts) group – Removed by concentrated acid (HBr, H₂SO₄) & strong reducing agents (sodium in liquid ammonia or sodium naphthalenide)
Other sulfonamide (Nosyl & Nps) groups — Removed by samarium iodide, thiophenol or other soft thiol nucleophiles, or tributyltin hydride^[59]

Benzylamines:

Benzyl (Bn) group – Removed by hydrogenolysis
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 (CAN)

Carbonyl protecting groups

The most common protecting groups for carbonyls are acetals and typically cyclic acetals with diols. The runners-up used are also cyclic acetals with 1,2‑hydroxythiols or dithioglycols – the so-called O,S– or S,S-acetals.

1,3‑Propadiol

Overall, trans-acetalation plays a lesser role in forming protective acetals; they are formed as a rule from glycols through dehydration. Normally a simple glycol like ethylene glycol or 1,3-propadiol is used for acetalation.Modern variants also use glycols, but with the hydroxyl hydrogens replaced with a trimethylsilyl group.^[60]^[61]

Acetals can be removed in acidic aqueous conditions. For those ends, the mineral acids are appropriate acids. Acetone is a common cosolvent, used to promote dissolution. For a non-acidic cleavage technique, a palladium(II) chloride acetonitrile complex in acetone^[62] or iron(III) chloride on silica gel can be performed with workup in chloroform.^[63]

Cyclic acetals are very much more stable against acid hydrolysis than acyclic acetals. Consequently acyclic acetals are used practically only when a very mild cleavage is required or when two different protected carbonyl groups must be differentiated in their liberation.^[64]

Besides the O,O-acetals, the S,O- and S,S-acetals also have an application, albeit scant, as carbonyl protecting groups too. Thiols, which one begins with to form these acetals, have a very unpleasant stench and are poisonous, which severely limit their applications. Thioacetals and the mixed S,O-acetals are, unlike the pure O,O-acetals, very much stabler against acid hydrolysis. This enables the selective cleavage of the latter in the presence of sulfur-protected carbonyl groups.

The formation of S,S-acetals normally follows analogously to the O,O-acetals with acid catalysis from a dithiol and the carbonyl compound. Because of the greater stability of thioacetals, the equilibirum lies on the side of the acetal. In contradistinction to the O,O‑acetal case, it is not needed to remove water from the reaction mixture in order to shift the equilibrium.^[65]

S,O-Acetals are hydrolyzed a factor of 10,000 times faster than the corresponding S,S-acetals. Their formation follows analogously from the thioalcohol. Also their cleavage proceeds under similar conditions and predominantly through mercury(II) compounds in wet acetonitrile.^[66]

For aldehydes, a temporary protection of the carbonyl group the presence of ketones as hemiaminal ions is shown below. Here it is applied, that aldehydes are very much more activated carbonyls than ketones and that many addition reactions are reversible.^[67]^[68]

Types of protectants

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

The most important protecting groups for carboxylic acids are the esters of various alcohols. Occasionally, esters are protected as ortho-esters or oxazolines.^[69]

Many groups can suffice for the alcoholic component, and the specific cleaving conditions are contrariwise generally quite similar: each ester can be hydrolyzed in a basic water-alcohol solution. Instead, most ester protecting groups vary in how mildly they can be formed from the original acid.

Protecting groups

Methyl esters — Also removed by acid^{[citation needed]} or pig liver esterase.^[70]^[71] Can be formed from diazomethane in diethyl ether,^[72]^[73]^[74] caesium carbonate and methyl iodide in N,N‑dimethylformamide,^[75] or methanol and catalytic trimethylsilyl chloride^[76]
Benzyl esters — Also removed by hydrogenolysis.^[77]
Benzhydryl esters — Same as benzyl, but easier to cleave^[78]
tert-Butyl esters – Also removed by acid^[79]^[80] and some reductants. Can be formed from carboalkoxylation: isobutene in dioxane and catalytic sulfuric acid^[81]^[82]^[83]
2,6‑Dialkylphenols (e.g. 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol) — Also removed in DBU-catalyzed high-pressure methanolysis at room temperature.^[84]
Allyl esters — As with allyl ethers, also removed by diverse platinum complexes – connected with acid workup^[85]
Silyl esters – Also removed by base and organometallic reagents.
Orthoesters – Converted to standard ester by mild aqueous acid
Oxazoline – 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

Alkene

Alkenes rarely need protection or are protected. They are as a rule only involved in undesired side reactions with electrophilic attack, isomerization or catalytic hydration. For alkenes two protecting groups are basically known:

Temporary halogenation with bromine to a trans‑1,2‑dibromoalkane: the regeneration of the alkene then follows with preservation of conformation via elemental zinc^[86]^[87]^[88]^[89]^[90] or with titanocene dichloride.^[91]
Protection through a Diels-Alder reaction: the transformation of an alkene with a diene leads to a cyclic alkene, which is nevertheless similarly endangered by electrophilic attack as the original alkene. The cleavage of a protecting diene proceeds thermically, for the Diels-Alder reaction is a reversible (equilibrium) reaction.^[92]^[93]^[94]

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

For alkynes there are in any case two types of protecting groups. For terminal alkynes it is sometimes important to mask the acidic hydrogen atom. This normally proceeds from deprotonation (via a strong base like methylmagnesium bromide or butyllithium in tetrahydrofuran/dimethylsulfoxide) and subsequently reaction with chlorotrimethylsilane to a terminally TMS-protected alkyne.^[95] Cleavage follows hydrolytically – with potassium carbonate in methanol – or with fluoride ions like for example with tetrabutylammonium fluoride.^[96]

In order to protect the triple bond itself, sometimes a transition metal-alkyne complex with dicobalt octacarbonyl is used. The release of the cobalt then follows from oxidation.^[97]^[98]^[99]^[100]^[101]

Other

Photolabile protecting groups As a proof of concept orthogonal deprotection is demonstrated in a photochemical transesterification by trimethylsilyldiazomethane utilizing the kinetic isotope effect:^[102]
Orthogonal protection Application in Photochemistry
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.^[103] In practical terms their use adds two steps (protection-deprotection sequence) to a synthesis, either or both of which can dramatically lower chemical yield. Crucially, added complexity impedes the use of synthetic total synthesis in drug 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^[104]^[105]^[106] according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):

Protected and unprotected syntheses of the marine alkaloid, hapalindole U.
Hideaki Muratake's 1990 synthesis using Tosyl protecting groups (shown in blue).	Phil Baran's protecting-group free synthesis, reported in 2007.

Industrial applications

Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g. sucralose (sweetener) or the Roche synthesis of oseltamivir (Tamiflu, an antiviral drug)

An important example of industrial applications of protecting group theory is the synthesis of ascorbic acid (Vitamin C) à la Reichstein.

In order to prevent oxidation of the secondary alcohols with potassium permanganate, they are protected via acetalation with acetone and then deprotected after the oxidation of the primary alcohols to carboxylic acids.^[107]

A very spectacular example application of protecting groups from natural product synthesis is the 1994 total synthesis of palytoxin acid by Yoshito Kishi's research group.^[108] Here 42 functional groups (39 hydroxyls, one diol, an amine group, and a carboxylic acid) required protection. These proceeded through 8 different protecting groups (a methyl ester, five acetals, 20 TBDMS esters, nine p‑methoxybenzyl ethers, four benzoates, a methyl hemiacetal, an acetone acetal and an SEM ester).^[109]

The introduction or modification of a protecting group occasionally influences the reactivity of the whole molecule. For example, diagrammed below is an excerpt of the synthesis of an analogue of Mitomycin C by Danishefsky.^[110]

The exchange of a protecting group from a methyl ether to a MOM-ether inhibits here the opening of an epoxide to an aldehyde.

Protecting group chemistry finds itself an important application in the automated synthesis of peptides and nucleosides. The technique was introduced in the field of peptide synthesis by Robert Bruce Merrifield in 1977.^[111] For peptide synthesis via automated machine, the orthogonality of the Fmoc group (basic cleavage), the tert‑butyl group (acidic cleavage) and diverse protecting groups for functional groups on the amino acid side-chains are used.^[112] Up to four different protecting groups per nucleobase are used for the automated synthesis of DNA and RNA sequences in the oligonucleotide synthesis. The procedure begins actually with redox chemistry at the protected phosphorus atom. A tricoordinate phosphorus, used on account of the high reactivity, is tagged with a cyanoethyl protecting group on a free oxygen. After the coupling step follows an oxidation to phosphate, whereby the protecting group stays attached. Free OH-groups, which did not react in the coupling step, are acetylated in an intermediate step. These additionally-introduced protecting groups then inhibit, that these OH-groups might couple in the next cycle.^[113]

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External links

[1] Theodora W. Greene; Peter G. M. Wuts (1999). Protecting Groups in Organic Synthesis (3 ed.). J. Wiley. ISBN 978-0-471-16019-9.

[2] Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2194; doi:10.1002/ange.19961081805 (in German).

[FMOC-3] Chan, Weng C.; White, Peter D. (2004). Fmoc Solid Phase Peptide Synthesis. Oxford University Press. ISBN 978-0-19-963724-9.

[4] Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.

[5] Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2195–2200; doi:10.1002/ange.19961081805 (in German).

[6] V.N. Rajasekharan Pillai: "Photoremovable Protecting Groups in Organic Synthesis", in: Synthesis, 1980, pp. 1–26.

[7] P.J. Kocieński: Protecting Groups, p. 29.

[8] P.J. Kocieński: Protecting Groups, p. 31.

[9] Tod K Jones, Robert A. Reamer, Richard Desmond, Sander G. Mills: "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (−)-FK-506", in: J. Am. Chem. Soc., 1990, 112, pp. 2998–3017; doi:10.1021/ja00164a023.

[10] Dieter Seebach, Hak-Fun Chow, Richard F.W. Jackson, Marius A. Sutter, Suvit Thaisrivongs, Jürg Zimmermann: "(+)-11,11′-Di-O-methylelaiophylidene – preparation from elaiophylin and total synthesis from (R)-3-hydroxybutyrate and (S)-malate", in: Liebigs Ann. Chem., 1986, pp. 1281–1308; doi:10.1002/jlac.198619860714.

[11] David A. Evans, Stephen W. Kaldor, Todd K. Jones, Jon Clardy, Thomas J. Stout: "Total synthesis of the macrolide antibiotic cytovaricin", in: J. Am. Chem. Soc., 1990, 112, pp. 7001–7031; doi:10.1021/ja00175a038.

[12] James A. Marshall, Richard Sedrani: "A convergent, highly stereoselective synthesis of a C-11-C-21 subunit of the macbecins", in: J. Org. Chem., 1991, 56, pp. 5496–5498; doi:10.1021/jo00019a004.

[JACS_1990_49913-13] James D. White, Motoji Kawasaki: "Total synthesis of (+)-latrunculin A", in: J. Am. Chem. Soc., 1990, 112, pp. 4991–4993; doi:10.1021/ja00168a071.

[14] Morris J. Robins, Vicente Samano, Mark D. Johnson: "Nucleic acid-related compounds. 58. Periodinane oxidation, selective primary deprotection, and remarkably stereoselective reduction of tert-butyldimethylsilyl-protected ribonucleosides. Synthesis of 9-(β-D-xylofuranosyl)adenine or 3'-deuterioadenosine from adenosine", in: J. Org. Chem., 1990, 55, pp. 410–412; doi:10.1021/jo00289a004.

[15] R. Roger F. Newton, Derek P. Reynolds, Colin F. Webb, Stanley M. Roberts: "A short and efficient total synthesis of (±) prostaglandin D₂ methyl ester involving a new method for the cleavage of a dimethyl-t-butylsilyl ether", in: J. Chem. Soc., Perkin Trans. 1, 1981, pp. 2055–2058; doi:10.1039/P19810002055.

[16] Kyriacos C. Nicolaou, R. A. Daines, T. K. Chakraborty: "Total synthesis of amphoteronolide B", in: J. Am. Chem. Soc., 1987, 109, pp. 2208–2210; doi:10.1021/ja00241a063.

[17] Leo A. Paquette, Annette M. Doherty, Christopher M. Rayner: "Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework", in: J. Am. Chem. Soc., 1991, 109, pp. 3910–3926; doi:10.1021/ja00036a045.

[18] P.J. Kocieński: Protecting Groups, p. 40.

[19] P.J. Kocieński: Protecting Groups, pp. 46–49.

[20] Michel Bessodes, Dimitri Komiotis, Kostas Antonakis: "Rapid and selective detritylation of primary alcohols using formic acid", in: Tetrahedron Lett., 1986, 27, pp. 579–580; doi:10.1016/S0040-4039(00)84045-9.

[21] B. Helferich: Carbonhydr. Chem. Biochem., 1948, 3, pp. 79.

[22] M.L. García, J. Pascual, L. Borràs, J.A. Andreu, E. Fos, D. Mauleón, G. Carganico, F. Arcamone: "Synthesis of new ether glycerophospholipids structurally related to modulator", in: Tetrahedron, 1991, 47, pp. 10023–10034; doi:10.1016/S0040-4020(01)96051-X.

[23] Yuji Oikawa, Tadao Yoshioka, Osamu Yonemitsu: "Specific removal of o-methoxybenzyl protection by DDQ oxidation", in: Tetrahedron Lett., 1982, 23, pp. 885–888; doi:10.1016/S0040-4039(00)86974-9.

[24] See literature for p‑methoxybenzyl.

[25] P.J. Kocieński: Protecting Groups, p. 77.

[26] H. Nagaoka, W. Rutsch, G. Schmidt, H. Ito, M.R. Johnson, Y. Kishi: "Total synthesis of rifamycins. 1. Stereocontrolled synthesis of the aliphatic building block", in: J. Am. Chem. Soc., 1980, 102, pp. 7962–7965; doi:10.1021/ja00547a037.

[27] W. Clark Still, Dominick Mobilio: "Synthesis of asperdiol", in: J. Org. Chem., 1983, 48, pp. 4785–4786; doi:10.1021/jo00172a070.

[28] Masahiro Hirama, Mitsuko Uei: "A chiral total synthesis of compactin", in: J. Am. Chem. Soc., 1982, 104, pp. 4251–4253; doi:10.1021/ja00379a037.

[29] W. Clark Still, Shizuaki Murata, Gilbert Revial, Kazuo Yoshihara: "Synthesis of the cytotoxic germacranolide eucannabinolide", in: J. Am. Chem. Soc., 1983, 105, pp. 625–627; doi:10.1021/ja00341a055.

[30] Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4-dimethoxycinnamyl alcohol and derivatives by Coriolus versicolor". FEMS Microbiology Letters. 24 (2–3): 225–229. doi:10.1111/j.1574-6968.1984.tb01309.x.

[31] Serge David, Annie Thieffry, Alain Veyrières: "A mild procedure for the regiospecific benzylation and allylation of polyhydroxy-compounds via their stannylene derivatives in non-polar solvents", in: J. Chem. Soc., Perkin Trans. 1, 1981, pp. 1796–1801; doi:10.1039/P19810001796.

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@@ Line 6: / Line 6: @@
 In many preparations of delicate [[organic compound]]s, specific parts of the molecules cannot survive the required reagents or chemical environments. These parts (functional groups) must be '''protected'''. For example, [[lithium aluminium hydride]] is a highly reactive reagent that usefully reduces [[ester]]s to [[Alcohol (chemistry)|alcohol]]s. 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, [[Biomolecule|biomolecules]] like [[Peptide|peptides]], [[Oligosaccharide|oligosaccharides]] or [[Nucleotide|nucleotides]] – may require protecting groups to order their assembly.  Also, cheap [[Chiral auxiliary|chiral protecting groups]] may often ''shorten'' an [[enantioselective synthesis]] (e.g. [[shikimic acid]] for [[oseltamivir]]).
+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, [[biomolecule]]s like [[peptide]]s, [[oligosaccharide]]s or [[nucleotide]]s – may require protecting groups to order their assembly.  Also, cheap [[Chiral auxiliary|chiral protecting groups]] may often ''shorten'' an [[enantioselective synthesis]] (e.g. [[shikimic acid]] for [[oseltamivir]]).
-As a rule, the introduction of a protecting group is straightforward.  The difficulties honestly lie in their stability and in selective removal.  Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.<ref>Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: ''[[Angewandte Chemie]]'', '''1996''', ''103'', pp.&nbsp;2194; [[doi:10.1002/ange.19961081805]] (in German).  </ref>
+As a rule, the introduction of a protecting group is straightforward.  The difficulties honestly lie in their stability and in selective removal.  Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.<ref>Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: ''[[Angewandte Chemie]]'', '''1996''', ''103'', pp.&nbsp;2194; [[doi:10.1002/ange.19961081805]] (in German).</ref>
 ==Orthogonal protection==
@@ Line 21: / Line 21: @@
 </gallery>
-A further important example of orthogonal protecting groups occurs in [[carbohydrate]] chemistry.  As carbohydrates or [[Hydroxyl group|hydroxyl groups]] exhibit very similar reactivities, a transformation that protects or deprotects a single hydroxy group must be possible for a successful synthesis.
+A further important example of orthogonal protecting groups occurs in [[carbohydrate]] chemistry.  As carbohydrates or [[hydroxyl group]]s exhibit very similar reactivities, a transformation that protects or deprotects a single hydroxy group must be possible for a successful synthesis.
 === Cleavage categorization ===
@@ Line 36: / Line 36: @@
 * 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.
-[[Lipase|Lipases]] and other enzymes cleave ethers at [[biological pH]] (5-9) and [[Body temperature|temperatures]] (30–40&nbsp;°C).  Because enzymes have very high substrate specificity, the method is quite rare, but extremely attractive.
+[[Lipase]]s and other enzymes cleave ethers at [[biological pH]] (5-9) and [[Body temperature|temperatures]] (30–40&nbsp;°C).  Because enzymes have very high substrate specificity, the method is quite rare, but extremely attractive.
-Catalytic [[hydrogenation]] removes a wide variety of [[Benzyl group|benzyl groups]]: ethers, esters, urethanes, carbonates, etc.
+Catalytic [[hydrogenation]] removes a wide variety of [[benzyl group]]s: 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]] (CAN) or [[dichlorodicyanobenzoquinone]] (DDQ).
 [[File:PMB_deprotection.svg|center|frameless|440x440px]]
 [[File:PMB_deprotection_mechanismn.svg|center|frameless|440x440px]]
-[[allyl group|Allyl compounds]] will [[Isomerization|isomerize]] to a vinyl group in the presence of [[Noble metal|noble metals]].  The residual [[enol ether]] (from a protected alcohol) or [[enamine]] (resp. amine) hydrolyzes in light acid.
+[[allyl group|Allyl compounds]] will [[Isomerization|isomerize]] to a vinyl group in the presence of [[noble metal]]s.  The residual [[enol ether]] (from a protected alcohol) or [[enamine]] (resp. amine) hydrolyzes in light acid.
 Photolabile protecting groups bear a [[chromophore]], which is activated through radiation with an appropriate wavelength and so can be removed.<ref>V.N. Rajasekharan Pillai: "Photoremovable Protecting Groups in Organic Synthesis", in: ''[[Synthesis (journal)|Synthesis]]'', '''1980''', pp.&nbsp;1–26.</ref>  For examples the ''o''-nitrobenzylgroup ought be listed here.
@@ Line 56: / Line 56: @@
 ===Alcohol protecting groups===
-The classical protecting groups for alcohols are [[Ester|esters]], deprotected by [[Nucleophile|nucleophiles]]; [[Organosilanols|triorganosilyl]] [[Silyl ether|ethers]], deprotected by acids and fluoride ions; and [[Acetal|(hemi)acetals]], deprotected by weak acids.  In rarer cases, a carbon [[ether]] might be used.
+The classical protecting groups for alcohols are [[ester]]s, deprotected by [[nucleophile]]s; [[Organosilanols|triorganosilyl]] [[Silyl ether|ethers]], deprotected by acids and fluoride ions; and [[Acetal|(hemi)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 ester|acetate]], [[Benzoate ester|benzoate]], and [[Pivalate ester|pivalate esters]], for these exhibit differential removal.  Sterically hindered esters are less susceptible to nucleophilic attack:
+The most important esters with common protecting-group use are the [[Acetate ester|acetate]], [[Benzoate ester|benzoate]], and [[pivalate ester]]s, for these exhibit differential removal.  Sterically hindered esters are less susceptible to nucleophilic attack:
 : Chloroacetyl > acetyl > benzoyl > pivaloyl
@@ Line 70: / Line 70: @@
 Esters:
 * [[Acetyl]] (Ac) – Removed by acid or base (see [[Acetoxy group]]).
 * [[Benzoyl]] (Bz) – Removed by acid or base, more stable than Ac group.
 * [[Pivaloyl]] (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
@@ Line 77: / Line 76: @@
 * {{Anchor|TBDMS}}[[Trimethylsilyl]] (TMS)&nbsp;— [[Potassium fluoride]], [[acetic acid]] or [[potassium carbonate]] in [[methanol]]<ref>P.J. Kocieński: ''Protecting Groups'', p.&nbsp;29.</ref>
 * [[Triethylsilyl group|Triethylsilyl]]&nbsp;— 10–100× stabler than a TMS group.<ref>P.J. Kocieński: ''Protecting Groups'', p.&nbsp;31.</ref>  Cleaved with trifluoroacetic acid in water/[[tetrahydrofuran]],<ref>Tod K Jones, Robert A. Reamer, Richard Desmond, Sander G. Mills: "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (−)-FK-506", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;2998–3017; [[doi:10.1021/ja00164a023]].</ref> acetic acid in water/tetrahydrofuran,<ref>Dieter Seebach, Hak-Fun Chow, Richard F.W. Jackson, Marius A. Sutter, Suvit Thaisrivongs, Jürg Zimmermann: "(+)-11,11{{prime}}-Di-O-methylelaiophylidene – preparation from elaiophylin and total synthesis from (R)-3-hydroxybutyrate and (S)-malate", in: ''[[Liebigs Ann. Chem.]]'', '''1986''', pp.&nbsp;1281–1308; [[doi:10.1002/jlac.198619860714]].</ref> or [[hydrogen fluoride]] in water or pyridine<ref>David A. Evans, Stephen W. Kaldor, Todd K. Jones, Jon Clardy, Thomas J. Stout: "Total synthesis of the macrolide antibiotic cytovaricin", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;7001–7031; [[doi:10.1021/ja00175a038]].</ref>
-* {{Anchor|TOM}}''tert''-Butyldimethylsilyl (TBDMS or TBS)&nbsp;— Cleaved with acetic acid in tetrahydrofuran/water,<ref>James A. Marshall, Richard Sedrani: "A convergent, highly stereoselective synthesis of a C-11-C-21 subunit of the macbecins", in: ''[[J. Org. Chem.]]'', '''1991''', ''56'', pp.&nbsp;5496–5498; [[doi:10.1021/jo00019a004]].</ref> Pyridinium tosylate in methanol,<ref name="JACS_1990_49912">James D. White, Motoji Kawasaki: "Total synthesis of (+)-[[latrunculin]] A", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;4991–4993; [[doi:10.1021/ja00168a071]].</ref> trifluoroacetic acid in water,<ref>Morris J. Robins, Vicente Samano, Mark D. Johnson: "Nucleic acid-related compounds. 58. Periodinane oxidation, selective primary deprotection, and remarkably stereoselective reduction of tert-butyldimethylsilyl-protected ribonucleosides. Synthesis of 9-(β-D-xylofuranosyl)adenine or 3'-deuterioadenosine from adenosine", in: ''[[J. Org. Chem.]]'', '''1990''', ''55'', pp.&nbsp;410–412; [[doi:10.1021/jo00289a004]].</ref> hydrofluoric acid in [[acetonitrile]],<ref>R. Roger F. Newton, Derek P. Reynolds, Colin F. Webb, Stanley M. Roberts: "A short and efficient total synthesis of (±) prostaglandin D<sub>2</sub> methyl ester involving a new method for the cleavage of a dimethyl-t-butylsilyl ether", in: ''[[J. Chem. Soc., Perkin Trans. 1]]'', '''1981''', pp.&nbsp;2055–2058; [[doi:10.1039/P19810002055]].</ref> pyridinium fluoride in tetrahydrofuran,<ref>Kyriacos C. Nicolaou, R. A. Daines, T. K. Chakraborty: "Total synthesis of amphoteronolide B", in: ''[[J. Am. Chem. Soc.]]'', '''1987''', ''109'', pp.&nbsp;2208–2210; [[doi:10.1021/ja00241a063]].</ref> [[tetrabutylammonium fluoride]] in THF.<ref>Leo A. Paquette, Annette M. Doherty, Christopher M. Rayner: "Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework", in: ''[[J. Am. Chem. Soc.]]'', '''1991''', ''109'', pp.&nbsp;3910–3926; [[doi:10.1021/ja00036a045]].</ref>  Commonly protects 2'-hydroxy function in [[oligonucleotide synthesis]].
+* {{Anchor|TOM}}''tert''-Butyldimethylsilyl (TBDMS or TBS)&nbsp;— Cleaved with acetic acid in tetrahydrofuran/water,<ref>James A. Marshall, Richard Sedrani: "A convergent, highly stereoselective synthesis of a C-11-C-21 subunit of the macbecins", in: ''[[J. Org. Chem.]]'', '''1991''', ''56'', pp.&nbsp;5496–5498; [[doi:10.1021/jo00019a004]].</ref> Pyridinium tosylate in methanol,<ref name="JACS_1990_49913">James D. White, Motoji Kawasaki: "Total synthesis of (+)-[[latrunculin]] A", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;4991–4993; [[doi:10.1021/ja00168a071]].</ref> trifluoroacetic acid in water,<ref>Morris J. Robins, Vicente Samano, Mark D. Johnson: "Nucleic acid-related compounds. 58. Periodinane oxidation, selective primary deprotection, and remarkably stereoselective reduction of tert-butyldimethylsilyl-protected ribonucleosides. Synthesis of 9-(β-D-xylofuranosyl)adenine or 3'-deuterioadenosine from adenosine", in: ''[[J. Org. Chem.]]'', '''1990''', ''55'', pp.&nbsp;410–412; [[doi:10.1021/jo00289a004]].</ref> hydrofluoric acid in [[acetonitrile]],<ref>R. Roger F. Newton, Derek P. Reynolds, Colin F. Webb, Stanley M. Roberts: "A short and efficient total synthesis of (±) prostaglandin D<sub>2</sub> methyl ester involving a new method for the cleavage of a dimethyl-t-butylsilyl ether", in: ''[[J. Chem. Soc., Perkin Trans. 1]]'', '''1981''', pp.&nbsp;2055–2058; [[doi:10.1039/P19810002055]].</ref> pyridinium fluoride in tetrahydrofuran,<ref>Kyriacos C. Nicolaou, R. A. Daines, T. K. Chakraborty: "Total synthesis of amphoteronolide B", in: ''[[J. Am. Chem. Soc.]]'', '''1987''', ''109'', pp.&nbsp;2208–2210; [[doi:10.1021/ja00241a063]].</ref> [[tetrabutylammonium fluoride]] in THF.<ref>Leo A. Paquette, Annette M. Doherty, Christopher M. Rayner: "Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework", in: ''[[J. Am. Chem. Soc.]]'', '''1991''', ''109'', pp.&nbsp;3910–3926; [[doi:10.1021/ja00036a045]].</ref>  Commonly protects 2'-hydroxy function in [[oligonucleotide synthesis]].
 * Triisopropylsilyl (TIPS) ethers)&nbsp;— Similar conditions to TBS but longer reaction times.<ref>P.J. Kocieński: ''Protecting Groups'', p.&nbsp;40.</ref>
 * ''tert''{{Nbh}}Butyldiphenylsilyl (TBDPS)&nbsp;— Similar conditions to TBS but even longer reaction times (100–250× slower than TBS and 5–10× slower than TIPS)
@@ Line 96: / Line 95: @@
 * [[Methoxymethyl ether]] (MOM)&nbsp;— Removed by 6&nbsp;M hydrochloric acid in tetrahydrofuran/water<ref>Paul A. Wender, Carlos R. D. Correia: "Intramolecular photoinduced diene-diene cyaloadditions: a selective method for the synthesis of complex eight-membered rings and polyquinanes", in: ''[[J. Am. Chem. Soc.]]'', '''1987''', ''109'', pp.&nbsp;2523–2525; [[doi:10.1021/ja00242a053]].</ref>
 * [[Tetrahydropyranyl]] (THP)&nbsp;— Removed by acetic acid in tetrahydrofuran/water,<ref>Karel F. Bernady, M. Brawner Floyd, John F. Poletto, Martin J. Weiss: "Prostaglandins and congeners. 20. Synthesis of prostaglandins via conjugate addition of lithium trans-1-alkenyltrialkylalanate reagents. A novel reagent for conjugate 1,4-additions", in: ''[[J. Org. Chem.]]'', '''1979''', ''44'', pp.&nbsp;1438–1447; [[doi:10.1021/jo01323a017]].</ref> ''p''{{nbh}}toluenesulfonic acid in methanol<ref>Elias J. Corey, Haruki Niwa, Jochen Knolle: "Total synthesis of (S)-12-hydroxy-5,8,14-cis,-10-trans-eicosatetraenoic acid (Samuelsson's HETE)", in: ''[[J. Am. Chem. Soc.]]'', '''1978''', ''100'', pp.&nbsp;1942–1943; [[doi:10.1021/ja00474a058]].</ref>
-* [[Methylthiomethyl ether]]&nbsp;— Removed by acid{{Cn|date=February 2024}} or [[HSAB theory|soft]] metal oxidants: base-buffered [[Mercury(II) chloride|mercuric chloride]] in wet acetonitrile<ref>Elias J. Corey, Mark G. Bock: "Protection of primary hydroxyl groups as methylthiomethyl ethers", in: ''[[Tetrahedron Lett.]]'', '''1975''', ''16'', pp.&nbsp;3269–3270; [[doi:10.1016/S0040-4039(00)91422-9]].</ref> or [[silver nitrate]] in wet tetrahydrofuran<ref>Elias J. Corey, Duy H. Hua, Bai Chuan Pan, Steven P. Seitz: "Total synthesis of aplasmomycin", in: ''[[J. Am. Chem. Soc.]]'', '''1982''', ''104'', pp.&nbsp;6818–6820; [[doi:10.1021/ja00388a074]].</ref>
+* [[Methylthiomethyl ether]]&nbsp;— Removed by acid{{Citation needed|date=February 2024}} or [[HSAB theory|soft]] metal oxidants: base-buffered [[Mercury(II) chloride|mercuric chloride]] in wet acetonitrile<ref>Elias J. Corey, Mark G. Bock: "Protection of primary hydroxyl groups as methylthiomethyl ethers", in: ''[[Tetrahedron Lett.]]'', '''1975''', ''16'', pp.&nbsp;3269–3270; [[doi:10.1016/S0040-4039(00)91422-9]].</ref> or [[silver nitrate]] in wet tetrahydrofuran<ref>Elias J. Corey, Duy H. Hua, Bai Chuan Pan, Steven P. Seitz: "Total synthesis of aplasmomycin", in: ''[[J. Am. Chem. Soc.]]'', '''1982''', ''104'', pp.&nbsp;6818–6820; [[doi:10.1021/ja00388a074]].</ref>
 * Tris(isopropyl)silyloxymethyl (TOM)&nbsp;— Commonly protects 2'-hydroxy function in [[oligonucleotide synthesis]].
-* [[(Trimethylsilyl)ethoxymethyl group|β{{nbh}}(Trimethylsilyl)ethoxymethyl]]&nbsp;— More labile than MEM and MOM to acid hydrolysis: 0.1&nbsp;M hydrochloric acid in methanol,<ref>Robert C. Gadwood, Renee M. Lett, Jane E. Wissinger: "Total synthesis of (±)-poitediol and (±)4-epipoitediol", in: ''[[J. Am. Chem. Soc.]]'', '''1984''', ''106'', pp.&nbsp;3869–3870; [[doi:10.1021/ja00325a032]].</ref> concentrated hydrofluoric acid in acetonitrile,<ref name="JACS_1990_49913">James D. White, Motoji Kawasaki: "Total synthesis of (+)-[[latrunculin]] A", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;4991–4993; [[doi:10.1021/ja00168a071]].</ref> boron trifluoride etherate in dichloromethane,<ref>Steven D. Burke, Gregory J. Pacofsky: "The ester enolate claisen rearrangement. Total synthesis of (±)-ethisolide", in: ''[[Tetrahedron Lett.]]'', '''1986''', ''27'', pp.&nbsp;445–448; [[doi:10.1016/S0040-4039(00)85501-X]].</ref> or [[tetrabutylammonium fluoride]] in HMPT ([[Hexamethyl phosphoric acid triamide]]) or in tetrahydrofuran<ref>Toshiyuki Kan, Masaru Hashimoto, Mitsutoshi Yanagiya, Haruhisa Shirahama: "Effective deprotection of 2-(trimethylsilylethoxy)methylated alcohols (SEM ethers). Synthesis of thyrsiferyl-23 acetate", in: ''[[Tetrahedron Lett.]]'', '''1988''', ''29'', pp.&nbsp;5417–5418; [[doi:10.1016/S0040-4039(00)82883-X]].</ref><ref>Joseph P. Marino, Scott L. Dax: "An efficient desilylation method for the generation of o-quinone methides: application to the synthesis of (+)- and (−)-hexahydrocannabinol", in: ''[[J. Org. Chem.]]'', '''1984''', ''49'', pp.&nbsp;3671–3672; [[doi:10.1021/jo00193a051]].</ref>
+* [[(Trimethylsilyl)ethoxymethyl group|β{{nbh}}(Trimethylsilyl)ethoxymethyl]]&nbsp;— More labile than MEM and MOM to acid hydrolysis: 0.1&nbsp;M hydrochloric acid in methanol,<ref>Robert C. Gadwood, Renee M. Lett, Jane E. Wissinger: "Total synthesis of (±)-poitediol and (±)4-epipoitediol", in: ''[[J. Am. Chem. Soc.]]'', '''1984''', ''106'', pp.&nbsp;3869–3870; [[doi:10.1021/ja00325a032]].</ref> concentrated hydrofluoric acid in acetonitrile,<ref name="JACS_1990_49913"/> boron trifluoride etherate in dichloromethane,<ref>Steven D. Burke, Gregory J. Pacofsky: "The ester enolate claisen rearrangement. Total synthesis of (±)-ethisolide", in: ''[[Tetrahedron Lett.]]'', '''1986''', ''27'', pp.&nbsp;445–448; [[doi:10.1016/S0040-4039(00)85501-X]].</ref> or [[tetrabutylammonium fluoride]] in HMPT ([[Hexamethyl phosphoric acid triamide]]) or in tetrahydrofuran<ref>Toshiyuki Kan, Masaru Hashimoto, Mitsutoshi Yanagiya, Haruhisa Shirahama: "Effective deprotection of 2-(trimethylsilylethoxy)methylated alcohols (SEM ethers). Synthesis of thyrsiferyl-23 acetate", in: ''[[Tetrahedron Lett.]]'', '''1988''', ''29'', pp.&nbsp;5417–5418; [[doi:10.1016/S0040-4039(00)82883-X]].</ref><ref>Joseph P. Marino, Scott L. Dax: "An efficient desilylation method for the generation of o-quinone methides: application to the synthesis of (+)- and (−)-hexahydrocannabinol", in: ''[[J. Org. Chem.]]'', '''1984''', ''49'', pp.&nbsp;3671–3672; [[doi:10.1021/jo00193a051]].</ref>
 Other ethers:
-* ''p''-Methoxyphenyl ether (PMP) – Removed by oxidation.{{Cn|date=February 2024}}
+* ''p''-Methoxyphenyl ether (PMP) – Removed by oxidation.{{Citation needed|date=February 2024}}
 * [[Butyl group#Tert-butyl as Protecting group|Tert-butyl ethers]] (tBu) – Removed with anhydrous trifluoroacetic acid, [[hydrogen bromide]] in acetic acid, or 4&nbsp;N hydrochloric acid<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;59–60.</ref>
 * [[Allyl group|Allyl]]&nbsp;— Removed with potassium ''tert''{{nbh}}butoxide<ref>P.J. Kocieński: ''Protecting Groups'', p.&nbsp;62.</ref> [[DABCO]] in methanol, palladium on activated carbon, or diverse platinum complexes – conjoined with acid workup.<ref>R.E. Ireland, D.W. Norbeck: "Convergent synthesis of polyether ionophore antibiotics: the synthesis of the monensin bis(tetrahydrofuran) via the Claisen rearrangement of an ester enolate with a β-leaving group", in: ''[[J. Am. Chem. Soc.]]'', '''1985''', ''107'', pp.&nbsp;3279–3285; [[doi:10.1021/ja00297a038]].</ref>
@@ Line 107: / Line 106: @@
 === 1,2-Diols ===
-The 1,2{{nbh}}diols ([[Glycol|glycols]]) 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 [[Benzyl group|benzylidene]], [[Isopropyl group|isopropylidene]] and [[Cyclohexyl group|cyclohexylidene]] or [[Cyclopentyl group|cyclopentylidene]] acetals.
+The 1,2{{nbh}}diols ([[glycol]]s) 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 [[Benzyl group|benzylidene]], [[Isopropyl group|isopropylidene]] and [[Cyclohexyl group|cyclohexylidene]] or [[Cyclopentyl group|cyclopentylidene]] acetals.
 [[File:Acetals_is.svg|alt=Applied acetal|center|400x400px]]
-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]] (DIBAL). The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.<ref>András Lipták, János Imre, János Harangi, Pál Nánási, András Neszmélyi: "Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-D-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH<sub>4</sub>-AlCl<sub>3</sub> reagent", in: ''[[Tetrahedron]]'', '''1982''', ''38'', pp.&nbsp;3721–3727; [[doi:10.1016/0040-4020(82)80083-5]].</ref><ref>James A. Marshall, Joseph D. Trometer, Bruce E. Blough, Thomas D. Crute: "Stereochemistry of SN2' additions to acyclic vinyloxiranes", in ''J. Org. Chem.'', '''1988''', ''53'', pp.&nbsp;4274–4282 [[doi:10.1021/jo00253a020]].</ref>
+An exceptional case appears with the benzylideneprotecting group,which also admits reductive cleavage.  This proceeds either through catalytic hydrogenation or with the hydride donor [[Diisobutylaluminium hydride|diisobutyl aluminum hydride]] (DIBAL). The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.<ref>András Lipták, János Imre, János Harangi, Pál Nánási, András Neszmélyi: "Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-D-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH<sub>4</sub>-AlCl<sub>3</sub> reagent", in: ''[[Tetrahedron]]'', '''1982''', ''38'', pp.&nbsp;3721–3727; [[doi:10.1016/0040-4020(82)80083-5]].</ref><ref>James A. Marshall, Joseph D. Trometer, Bruce E. Blough, Thomas D. Crute: "Stereochemistry of SN2' additions to acyclic vinyloxiranes", in ''J. Org. Chem.'', '''1988''', ''53'', pp.&nbsp;4274–4282 [[doi:10.1021/jo00253a020]].</ref>
 [[File:DIBAL_cleavage_of_benzylidenacetales_is.svg|alt=Cleaving a benzylidene acetal with DIBAL|center|400x400px]]
@@ Line 115: / Line 114: @@
 [[File:Tert-Butoxycarbonyl protected Glycine Structural Formulae V.1.png|thumb|250px|BOC [[glycine]]. The ''tert''-butyloxycarbonyl group is marked <span style="color:blue;">'''blue'''</span>.]]Amines have a special importance in [[peptide synthesis]], but are a quite potent [[nucleophile]] and also relatively strong [[Base (chem)|bases]].  These characteristics imply that new protecting groups for amines are always under development.<ref>P.J. Kocieński: ''Protecting Groups'', p.&nbsp;186.</ref>
-[[Amine group|Amine groups]] are primarily protected through [[acylation]], typically as a [[carbamate]].  When a carbamate deprotects, it evolves [[carbon dioxide]].  The commonest-used carbamates are the ''tert''-butoxycarbonyl, benzoxycarbonyl, fluorenylmethylenoxycarbonyl, and allyloxycarbonyl compounds.
+[[Amine group]]s are primarily protected through [[acylation]], typically as a [[carbamate]].  When a carbamate deprotects, it evolves [[carbon dioxide]].  The commonest-used carbamates are the ''tert''-butoxycarbonyl, benzoxycarbonyl, fluorenylmethylenoxycarbonyl, and allyloxycarbonyl compounds.
-Other, more exotic amine protectors are the [[Phthalimide|phthalimides]], which admit reductive cleavage,<ref>John O. Osby, Michael G. Martin, Bruce Ganem: ''An Exceptionally Mild Deprotection of Phthalimides'', in: ''[[Tetrahedron Lett.]]'', '''1984''', ''25'', pp.&nbsp;2093–2096; [[doi:10.1016/S0040-4039(01)81169-2]].</ref> and the trifluoroacetamides, which hydrolyze easily in base.  [[Indole|Indoles]], [[Pyrrole|pyrroles]] und [[Imidazole|imidazoles]]&nbsp;— verily any aza-heterocycle&nbsp;— admit protection as ''N''{{nbh}}sulfonylamides,which are far too stable with aliphatic amines.<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;220–227.</ref>  ''N''{{nbh}}benzylated amines can be removed through [[catalytic hydrogenation]] or Birch reduction, but have a decided drawback relative to the carbamates or amides: they retain a basic nitrogen.
+Other, more exotic amine protectors are the [[phthalimide]]s, which admit reductive cleavage,<ref>John O. Osby, Michael G. Martin, Bruce Ganem: ''An Exceptionally Mild Deprotection of Phthalimides'', in: ''[[Tetrahedron Lett.]]'', '''1984''', ''25'', pp.&nbsp;2093–2096; [[doi:10.1016/S0040-4039(01)81169-2]].</ref> and the trifluoroacetamides, which hydrolyze easily in base.  [[Indole]]s, [[pyrrole]]s und [[imidazole]]s&nbsp;— verily any aza-heterocycle&nbsp;— admit protection as ''N''{{nbh}}sulfonylamides,which are far too stable with aliphatic amines.<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;220–227.</ref>  ''N''{{nbh}}benzylated amines can be removed through [[catalytic hydrogenation]] or Birch reduction, but have a decided drawback relative to the carbamates or amides: they retain a basic nitrogen.
 ==== Selection ====
@@ Line 125: / Line 124: @@
 * [[Methoxybenzyl|''p''-Methoxybenzyloxycarbonyl]] (Moz or MeOZ) group – Removed by [[hydrogenolysis]], more labile than Cbz
 * [[Tert-butyloxycarbonyl protecting group|''tert''-Butyloxycarbonyl]] (Boc) group&nbsp;— Removed by concentrated strong acid (such as HCl<ref>Glenn L. Stahl, Roderich Walter, Clarck W. Smith: "General procedure for the synthesis of mono-N-acylated 1,6-diaminohexanes", in: ''[[J. Org. Chem.]]'', '''1978''', ''43'', pp.&nbsp;2285–2286; [[doi:10.1021/jo00405a045]].</ref> or CF<sub>3</sub>COOH<ref>Naomi Sakai, Yasufumi Ohfune: "Total synthesis of galantin I. Acid-catalyzed cyclization of galantinic acid", in: ''[[J. Am. Chem. Soc.]]'', '''1992''', ''114'', pp.&nbsp;998–1010; [[doi:10.1021/ja00029a031]].</ref>), or by heating to >80&nbsp;°C.  Common in [[solid phase peptide synthesis]].
-* 9-Fluorenylmethyloxycarbonyl ([[Fmoc]]) group&nbsp;— Removed by base, such as 20–50&nbsp;% [[piperidine]] in [[dimethylformamide]] (DMF)<ref>Weng C. Chan, Peter D. White: ''Fmoc Solid Phase Peptide Synthesis'', pp.&nbsp;27–30.</ref> or [[N-Methyl-2-pyrrolidone|''N''-Methyl-2-pyrrolidone]],<ref>Gregg B. Fields: [http://www.renyi.hu/~stipsicz/skin/PepsynthProt/Ch_2.pdf ''Methods for Removing the Fmoc Group.''] (PDF; 663&nbsp;kB) In: Michael W. Pennington, Ben M. Dunn (eds.): ''Peptide Synthesis Protocols''  volume 35, 1995, ISBN 978-0-89603-273-6, pp.&nbsp;17–27.</ref> or 50&nbsp;% [[morpholine]] in DMF for sensitive [[Glycoproteins|glycopeptides]].<ref>B. Liebe, H. Kunz: ''Festphasensynthese eines tumorassoziierten Sialyl-Tn-Antigen-Glycopeptids mit einer Partialsequenz aus dem "Tandem Repeat" des MUC-1-Mucins'' In: ''Angew. Chem.'' volume 109, 1997, pp.&nbsp;629–631 (in German).</ref><ref>ChemPep Inc.: [http://www.chempep.com/ChemPep-Fmoc-Solid-Phase-Peptide-Synthesis.htm ''Fmoc Solid Phase Peptide Synthesis.''] retrieved 16 November 2013.</ref>  Common in [[solid phase peptide synthesis]]
+* 9-Fluorenylmethyloxycarbonyl ([[Fmoc]]) group&nbsp;— Removed by base, such as 20–50&nbsp;% [[piperidine]] in [[dimethylformamide]] (DMF)<ref>Weng C. Chan, Peter D. White: ''Fmoc Solid Phase Peptide Synthesis'', pp.&nbsp;27–30.</ref> or [[N-Methyl-2-pyrrolidone|''N''-Methyl-2-pyrrolidone]],<ref>Gregg B. Fields: [http://www.renyi.hu/~stipsicz/skin/PepsynthProt/Ch_2.pdf ''Methods for Removing the Fmoc Group.''] (PDF; 663&nbsp;kB) In: Michael W. Pennington, Ben M. Dunn (eds.): ''Peptide Synthesis Protocols''  volume 35, 1995, ISBN 978-0-89603-273-6, pp.&nbsp;17–27.</ref> or 50% [[morpholine]] in DMF for sensitive [[Glycoproteins|glycopeptides]].<ref>B. Liebe, H. Kunz: ''Festphasensynthese eines tumorassoziierten Sialyl-Tn-Antigen-Glycopeptids mit einer Partialsequenz aus dem "Tandem Repeat" des MUC-1-Mucins'' In: ''Angew. Chem.'' volume 109, 1997, pp.&nbsp;629–631 (in German).</ref><ref>ChemPep Inc.: [http://www.chempep.com/ChemPep-Fmoc-Solid-Phase-Peptide-Synthesis.htm ''Fmoc Solid Phase Peptide Synthesis.''] retrieved 16 November 2013.</ref>  Common in [[solid phase peptide synthesis]]
 * [[Allyloxycarbonyl group|Allyloxycarbamate]] group&nbsp;— Removed with complexes of metals like palladium(0) or [[nickel]](0).<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;199–201.</ref>
 Other amides:
@@ Line 141: / Line 140: @@
 The most common protecting groups for carbonyls are acetals and typically cyclic acetals with diols.  The runners-up used are also cyclic acetals with 1,2{{nbh}}hydroxythiols or dithioglycols&nbsp;– the so-called ''O'',''S''– or ''S'',''S''-acetals.[[File:Ethylenglycol_is.svg|thumb|Ethylene glycol]]
 [[File:1,3-Propanediol.svg|thumb|1,3{{nbh}}Propadiol]]
 Overall, trans-acetalation plays a lesser role in forming protective acetals; they are formed as a rule from glycols through dehydration.  Normally a simple glycol like [[ethylene glycol]] or [[1,3-propadiol]] is used for acetalation.Modern variants also use glycols, but with the hydroxyl hydrogens replaced with a trimethylsilyl group.<ref>T. Tsunoda, M. Suzuki, R. Noyori: "A facile procedure for acetalization under aprotic conditions", in: ''[[Tetrahedron Lett.]]'', '''1980''', ''21'', pp.&nbsp;1357–1358; [[doi:10.1016/S0040-4039(00)74575-8]].</ref><ref>Juji Yoshimura, Shigeomi Horito, Hiroriobu Hashimoto: "Facile Synthesis of 2,3,4,6-Tetra-O-benzyl-D-glucopyranosylidene Acetals Using Trimethylsilyl Trifluoromethanesulfonate Catalyst", in: ''[[Chem. Lett.]]'', '''1981''', ''10'', pp.&nbsp;375–376; [[doi:10.1246/cl.1981.375]].</ref>
 Acetals can be removed in acidic aqueous conditions.  For those ends, the mineral acids are appropriate acids.  [[Acetone]] is a common cosolvent, used to promote dissolution.  For a non-acidic cleavage technique, a [[palladium(II) chloride]] acetonitrile complex in acetone<ref>Bruce H. Lipshutz, Daniel Pollart, Joseph Monforte, Hiyoshizo Kotsuki: "Pd(II)-catalyzed acetal/ketal hydrolysis/exchange reactions", in: ''[[Tetrahedron Lett.]]'', '''1985''', ''26'', pp.&nbsp;705–708; [[doi:10.1016/S0040-4039(00)89114-5]].</ref> or [[iron(III) chloride]] on [[silica gel]] can be performed with workup in chloroform.<ref>Kwan Soo Kim, Yang Heon Song, Bong Ho Lee, Chi Sun Hahn: "Efficient and selective cleavage of acetals and ketals using ferric chloride adsorbed on silica gel", in: ''[[J. Org. Chem.]]'', '''1986''', ''51'', pp.&nbsp;404–407; [[doi:10.1021/jo00353a027]].</ref>
@@ Line 147: / Line 146: @@
 Cyclic acetals are very much more stable against acid hydrolysis than acyclic acetals.  Consequently acyclic acetals are used practically only when a very mild cleavage is required or when two different protected carbonyl groups must be differentiated in their liberation.<ref>P.J. Kocieński: ''Protecting Groups'', S.&nbsp;167–170.</ref>
-Besides the ''O'',''O''-acetals, the ''S'',''O''- and ''S'',''S''-acetals also have an application, albeit scant, as carbonyl protecting groups too. [[Thiol|Thiols]], which one begins with to form these acetals, have a very unpleasant stench and are poisonous, which severely limit their applications. [[Thioacetal|Thioacetals]] and the mixed ''S'',''O''-acetals are, unlike the pure ''O'',''O''-acetals, very much stabler against acid hydrolysis.  This enables the selective cleavage of the latter in the presence of [[sulfur]]-protected carbonyl groups.
+Besides the ''O'',''O''-acetals, the ''S'',''O''- and ''S'',''S''-acetals also have an application, albeit scant, as carbonyl protecting groups too. [[Thiol]]s, which one begins with to form these acetals, have a very unpleasant stench and are poisonous, which severely limit their applications. [[Thioacetal]]s and the mixed ''S'',''O''-acetals are, unlike the pure ''O'',''O''-acetals, very much stabler against acid hydrolysis.  This enables the selective cleavage of the latter in the presence of [[sulfur]]-protected carbonyl groups.
 The formation of ''S'',''S''-acetals normally follows analogously to the ''O'',''O''-acetals with acid catalysis from a dithiol and the carbonyl compound. Because of the greater stability of thioacetals, the equilibirum lies on the side of the acetal.  In contradistinction to the ''O'',''O''{{nbh}}acetal case, it is not needed to remove water from the reaction mixture in order to shift the equilibrium.<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;176.</ref>
@@ Line 162: / Line 161: @@
 ===Carboxylic acid protecting groups===
-The most important protecting groups for [[Carboxylic acid|carboxylic acids]] are the esters of various alcohols.  Occasionally, esters are protected as ortho-esters or [[oxazoline|oxazolines]].<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;119.</ref>
+The most important protecting groups for [[carboxylic acid]]s are the esters of various alcohols.  Occasionally, esters are protected as ortho-esters or [[oxazoline]]s.<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;119.</ref>
 Many groups can suffice for the alcoholic component, and the specific cleaving conditions are contrariwise generally quite similar: each ester can be hydrolyzed in a basic water-alcohol solution. Instead, most ester protecting groups vary in how mildly they can be formed from the original acid.
 ==== Protecting groups ====
-* [[Methyl]] [[esters]]&nbsp;— Also removed by acid{{Cn|date=February 2024}} or [[pig liver esterase]].<ref>Peter Mohr, Nada Waespe-Šarčević, Christoph Tamm, Krystyna Gawronska, Jacek K. Gawronski: "A Study of Stereoselective Hydrolysis of Symmetrical Diesters with Pig Liver Esterase", in: ''[[Helv. Chim. Acta]]'', '''1983''', ''66'', pp.&nbsp;2501–2511; [[doi:10.1002/hlca.19830660815]].</ref><ref>Théophile Tschamber, Nada Waespe-Šarčević, Christoph Tamm: "Stereocontrolled Synthesis of an Epimer of the C(19)-to-C(27) Segment of Rifamycin S", in: ''[[Helv. Chim. Acta]]'', '''1986''', ''69'', pp.&nbsp;621–625; [[doi:10.1002/hlca.19860690311]].</ref>  Can be formed from diazomethane in diethyl ether,<ref>Yves Rubin, Carolyn B. Knobler, Francois Diederich: "Precursors to the cyclo[n]carbons: from 3,4-dialkynyl-3-cyclobutene-1,2-diones and 3,4-dialkynyl-3-cyclobutene-1,2-diols to cyclobutenodehydroannulenes and higher oxides of carbon", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;1607–1617; [[doi:10.1021/ja00160a047]].</ref><ref>Sunggak Kim, Yong Gil Kim, Deog-il Kim: "A novel method for selective dioxolanation of ketones in the presence of aldehydes", in: ''[[Tetrahedron Lett.]]'', '''1992''', ''33'', pp.&nbsp;2565–2566; [[doi:10.1016/S0040-4039(00)92243-3]].</ref><ref>G. Bauduin, D. Bondon, Y. Pietrasanta, B. Pucci: "Reactions de transcetalisation – II: Influence des facteurs steriques et electroniques sur les energies de cetalisation", in: ''[[Tetrahedron]]'', '''1978''', ''34'', pp.&nbsp;3269–3274; [[doi:10.1016/0040-4020(78)80243-9]].</ref> [[caesium carbonate]] and methyl iodide in ''N'',''N''{{nbh}}dimethylformamide,<ref>John E. McMurry, Stephen J. Isser: "Total synthesis of longifolene", in: ''[[J. Am. Chem. Soc.]]'', '''1972''', ''94'', pp.&nbsp;7132–7137; [[doi:10.1021/ja00775a044]].</ref> or methanol and catalytic trimethylsilyl chloride<ref>M.P. Bosch, M. Pilar Bosch, Francisco Camps, Jose Coll, Angel Guerrero, Toshio Tatsuoka, Jerrold Meinwald: "A stereoselective total synthesis of (±)-muzigadial", in: ''[[J. Org. Chem.]]'', '''1986''', ''51'', pp.&nbsp;773–784; [[doi:10.1021/jo00356a002]].</ref>
+* [[Methyl]] [[esters]]&nbsp;— Also removed by acid{{Citation needed|date=February 2024}} or [[pig liver esterase]].<ref>Peter Mohr, Nada Waespe-Šarčević, Christoph Tamm, Krystyna Gawronska, Jacek K. Gawronski: "A Study of Stereoselective Hydrolysis of Symmetrical Diesters with Pig Liver Esterase", in: ''[[Helv. Chim. Acta]]'', '''1983''', ''66'', pp.&nbsp;2501–2511; [[doi:10.1002/hlca.19830660815]].</ref><ref>Théophile Tschamber, Nada Waespe-Šarčević, Christoph Tamm: "Stereocontrolled Synthesis of an Epimer of the C(19)-to-C(27) Segment of Rifamycin S", in: ''[[Helv. Chim. Acta]]'', '''1986''', ''69'', pp.&nbsp;621–625; [[doi:10.1002/hlca.19860690311]].</ref>  Can be formed from diazomethane in diethyl ether,<ref>Yves Rubin, Carolyn B. Knobler, Francois Diederich: "Precursors to the cyclo[n]carbons: from 3,4-dialkynyl-3-cyclobutene-1,2-diones and 3,4-dialkynyl-3-cyclobutene-1,2-diols to cyclobutenodehydroannulenes and higher oxides of carbon", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp.&nbsp;1607–1617; [[doi:10.1021/ja00160a047]].</ref><ref>Sunggak Kim, Yong Gil Kim, Deog-il Kim: "A novel method for selective dioxolanation of ketones in the presence of aldehydes", in: ''[[Tetrahedron Lett.]]'', '''1992''', ''33'', pp.&nbsp;2565–2566; [[doi:10.1016/S0040-4039(00)92243-3]].</ref><ref>G. Bauduin, D. Bondon, Y. Pietrasanta, B. Pucci: "Reactions de transcetalisation – II: Influence des facteurs steriques et electroniques sur les energies de cetalisation", in: ''[[Tetrahedron]]'', '''1978''', ''34'', pp.&nbsp;3269–3274; [[doi:10.1016/0040-4020(78)80243-9]].</ref> [[caesium carbonate]] and methyl iodide in ''N'',''N''{{nbh}}dimethylformamide,<ref>John E. McMurry, Stephen J. Isser: "Total synthesis of longifolene", in: ''[[J. Am. Chem. Soc.]]'', '''1972''', ''94'', pp.&nbsp;7132–7137; [[doi:10.1021/ja00775a044]].</ref> or methanol and catalytic trimethylsilyl chloride<ref>M.P. Bosch, M. Pilar Bosch, Francisco Camps, Jose Coll, Angel Guerrero, Toshio Tatsuoka, Jerrold Meinwald: "A stereoselective total synthesis of (±)-muzigadial", in: ''[[J. Org. Chem.]]'', '''1986''', ''51'', pp.&nbsp;773–784; [[doi:10.1021/jo00356a002]].</ref>
 * [[Benzyl]] esters&nbsp;— Also removed by hydrogenolysis.<ref>F. Zymalkokowski: ''Katalytische Hydrierung'', Ferdinand Enke Verlag, Stuttgart 1965, pp.&nbsp;127–133.</ref>
 * [[Benzhydryl compounds|Benzhydryl]] esters&nbsp;— Same as benzyl, but easier to cleave<ref>P.J. Kocieński: ''Protecting Groups'', pp.&nbsp;136.</ref>
@@ Line 180: / Line 179: @@
 Alkenes rarely need protection or are protected. They are as a rule only involved in undesired side reactions with [[Electrophile|electrophilic]] attack, [[isomerization]] or catalytic hydration. For alkenes two protecting groups are basically known:
-* Temporary halogenation with bromine to a ''trans''{{nbh}}1,2{{nbh}}dibromoalkane: the regeneration of the alkene then follows with preservation of conformation via elemntal [[zinc]]<ref>Ahmed M. Tafesh, Jens Weiguny: "A Review of the Selective Catalytic Reduction of Aromatic Nitro Compounds into Aromatic Amines, Isocyanates, Carbamates, and Ureas Using CO", in: ''[[Chem. Rev.]]'', '''1996''', ''96'', pp.&nbsp;2035–2052; [[doi:10.1021/cr950083f]].</ref><ref>Evan L. Allred, Boyd R. Beck, Kent J. Voorhees: "Formation of carbon-carbon double bonds by the reaction of vicinal dihalides with sodium in ammonia", in: ''[[J. Org. Chem.]]'', '''1974''', ''39'', pp.&nbsp;1426–1427; [[doi:10.1021/jo00926a024]].</ref><ref>Timothy S. Butcher, Feng Zhou, Michael R. Detty: "Debrominations of vic-Dibromides with Diorganotellurides. 1. Stereoselectivity, Relative Rates, and Mechanistic Implications", in: ''[[J. Org. Chem.]]'', '''1998''', ''63'', pp.&nbsp;169–176; [[doi:10.1021/jo9713363]].</ref><ref>C. J. Li, David N. Harpp: "Bis(triphenylstanyl)telluride a mild and selective reagent for telluration and debromination", in: ''[[Tetrahedron Lett.]]'', '''1990''', ''31'', pp.&nbsp;6291–6293; [[doi:10.1016/S0040-4039(00)97045-X]].</ref><ref>Corrado Malanga, Serena Mannucci, Luciano Lardicci: "Carbon-halogen bond activation by nickel catalyst: Synthesis of alkenes, from 1,2-dihalides", in: ''[[Tetrahedron]]'', '''1998''', ''54'', pp.&nbsp;1021–1028; [[doi:10.1016/S0040-4020(97)10203-4]].</ref>or with [[titanocene dichloride]].<ref>Byung Woo Yoo, Seo Hee Kim, Jun Ho Kim: "A Mild, Efficient, and Selective Debromination of vic-Dibromides to Alkenes with Cp<sub>2</sub>TiCl<sub>2</sub>/Ga System", in: ''[[Bull. Korean Chem. Soc.]]'', '''2010''', ''31'', pp.&nbsp;2757–2758; [[doi:10.5012/bkcs.2010.31.10.2757]].</ref>
+* Temporary halogenation with bromine to a ''trans''{{nbh}}1,2{{nbh}}dibromoalkane: the regeneration of the alkene then follows with preservation of conformation via elemental [[zinc]]<ref>Ahmed M. Tafesh, Jens Weiguny: "A Review of the Selective Catalytic Reduction of Aromatic Nitro Compounds into Aromatic Amines, Isocyanates, Carbamates, and Ureas Using CO", in: ''[[Chem. Rev.]]'', '''1996''', ''96'', pp.&nbsp;2035–2052; [[doi:10.1021/cr950083f]].</ref><ref>Evan L. Allred, Boyd R. Beck, Kent J. Voorhees: "Formation of carbon-carbon double bonds by the reaction of vicinal dihalides with sodium in ammonia", in: ''[[J. Org. Chem.]]'', '''1974''', ''39'', pp.&nbsp;1426–1427; [[doi:10.1021/jo00926a024]].</ref><ref>Timothy S. Butcher, Feng Zhou, Michael R. Detty: "Debrominations of vic-Dibromides with Diorganotellurides. 1. Stereoselectivity, Relative Rates, and Mechanistic Implications", in: ''[[J. Org. Chem.]]'', '''1998''', ''63'', pp.&nbsp;169–176; [[doi:10.1021/jo9713363]].</ref><ref>C. J. Li, David N. Harpp: "Bis(triphenylstanyl)telluride a mild and selective reagent for telluration and debromination", in: ''[[Tetrahedron Lett.]]'', '''1990''', ''31'', pp.&nbsp;6291–6293; [[doi:10.1016/S0040-4039(00)97045-X]].</ref><ref>Corrado Malanga, Serena Mannucci, Luciano Lardicci: "Carbon-halogen bond activation by nickel catalyst: Synthesis of alkenes, from 1,2-dihalides", in: ''[[Tetrahedron]]'', '''1998''', ''54'', pp.&nbsp;1021–1028; [[doi:10.1016/S0040-4020(97)10203-4]].</ref> or with [[titanocene dichloride]].<ref>Byung Woo Yoo, Seo Hee Kim, Jun Ho Kim: "A Mild, Efficient, and Selective Debromination of vic-Dibromides to Alkenes with Cp<sub>2</sub>TiCl<sub>2</sub>/Ga System", in: ''[[Bull. Korean Chem. Soc.]]'', '''2010''', ''31'', pp.&nbsp;2757–2758; [[doi:10.5012/bkcs.2010.31.10.2757]].</ref>
 * Protection through a [[Diels-Alder reaction]]: the transformation of an alkene with a diene leads to a cyclic alkene, which is nevertheless similarly endangered by electrophilic attack as the original alkene. The cleavage of a protecting diene proceeds thermically, for the Diels-Alder reaction is a reversible (equilibrium) reaction.<ref>Antonius J. H. Klunder, Jie Zhu, Binne Zwanenburg: "The Concept of Transient Chirality in the Stereoselective Synthesis of Functionalized Cycloalkenes Applying the Retro-Diels-Alder Methodology", in: ''[[Chem. Rev.]]'', '''1999''', ''99'', pp.&nbsp;1163–1190; [[doi:10.1021/cr9803840]].</ref><ref>Hideyuki Tanaka, Takashi Kamikubo, Naoyuki Yoshida, Hideki Sakagami, Takahiko Taniguchi, Kunio Ogasawara: "Enantio- and Diastereocontrolled Synthesis of (−)-Iridolactone and (+)-Pedicularis-lactone", in: ''[[Org. Lett.]]'', '''2001''', ''3'', pp.&nbsp;679–681; [[doi:10.1021/ol0070029]].</ref><ref>Martin Banwell, David Hockless, Bevyn Jarrott, Brian Kelly, Andrew Knill, Robert Longmore, Gregory Simpson: "Chemoenzymatic approaches to the decahydro-as-indacene cores associated with the spinosyn class of insecticide", in: ''[[J. Chem. Soc., Perkin Trans. 1]]'', '''2000''', pp.&nbsp;3555–3558; [[doi:10.1039/b006759h]].</ref>
@@ Line 193: / Line 192: @@
 [[File:Alkin_tms_is.svg|center|500x500px|Alkyne TMS protection]]
 In order to protect the triple bond itself, sometimes a transition metal-alkyne complex with [[dicobalt octacarbonyl]] is used. The release of the cobalt then follows from oxidation.<ref>Barry J. Teobald: "The Nicholas reaction: the use of dicobalt hexacarbonyl-stabilised propargylic cations in synthesis", in: ''[[Tetrahedron]]'', '''2002''', ''58'', pp.&nbsp;4133–4170; [[doi:10.1016/S0040-4020(02)00315-0]].</ref><ref>Kenneth M. Nicholas, R. Pettit: "An alkyne protection group", in: ''[[Tetrahedron Lett.]]'', '''1971''', ''37'', pp.&nbsp;3475–3478; [[doi:10.1016/S0040-4039(01)97209-0]].</ref><ref>Richard E. Connor, Kenneth M. Nicholas: "Isolation, characterization, and stability of α-[(ethynyl)dicobalt hexacarbonyl] carbonium ions", in: ''[[J. Organomet. Chem.]]'', '''1977''', ''125'', C45–C48; [[doi:10.1016/S0022-328X(00)89454-1]].</ref><ref>Rosa F. Lockwood, Kenneth M. Nicholas: "Transition metal-stabilized carbenium ions as synthetic intermediates. I. α-[(alkynyl)dicobalt hexacarbonyl] carbenium ions as propargylating agents", in: ''[[Tetrahedron Lett.]]'', '''1977''', pp.&nbsp;4163–4166; [[doi:10.1016/S0040-4039(01)83455-9]].</ref><ref>K.M. Nicholas, R. Pettit: "On the stability of α-(alkynyl)dicobalt hexacarbonyl carbonium ions", in: ''[[J. Organomet. Chem.]]'', '''1972''', ''44'', C21–C24; [[doi:10.1016/0022-328X(72)80037-8]].</ref>
-[[File:Alkin_Co_schützung_is.svg|alt=Alkyne protection with Co|center|500x500px]]
 ===Other===
 <ul>
+<li>
-<li><p>[[Photolabile Protecting Groups|Photolabile protecting groups]]</p>
-<p>As a [[proof of concept]] orthogonal deprotection is demonstrated in a [[photochemical]] [[transesterification]] by [[trimethylsilyldiazomethane]] utilizing the [[kinetic isotope effect]]:<ref>{{Cite journal |last1=Blanc |first1=Aurélien |last2=Bochet |first2=Christian G. |date=2007 |title=Isotope Effects in Photochemistry: Application to Chromatic Orthogonality |url=http://doc.rero.ch/record/8583/files/bochet_iep.pdf |journal=[[Org. Lett.]] |volume=9 |issue=14 |pages=2649–2651 |doi=10.1021/ol070820h |pmid=17555322}}</ref>  [[Image:OrthogonalprotectionApplicationInPhotochemistry.png|upright=1.35|center|frameless|Orthogonal protection Application in Photochemistry]]  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&nbsp;nm the other monoarene is obtained.</p></li>
+[[Photolabile Protecting Groups|Photolabile protecting groups]]
+As a [[proof of concept]] orthogonal deprotection is demonstrated in a [[photochemical]] [[transesterification]] by [[trimethylsilyldiazomethane]] utilizing the [[kinetic isotope effect]]:<ref>{{Cite journal |last1=Blanc |first1=Aurélien |last2=Bochet |first2=Christian G. |date=2007 |title=Isotope Effects in Photochemistry: Application to Chromatic Orthogonality |url=http://doc.rero.ch/record/8583/files/bochet_iep.pdf |journal=[[Org. Lett.]] |volume=9 |issue=14 |pages=2649–2651 |doi=10.1021/ol070820h |pmid=17555322}}</ref>  [[Image:OrthogonalprotectionApplicationInPhotochemistry.png|upright=1.35|center|frameless|Orthogonal protection Application in Photochemistry]]  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&nbsp;nm the other monoarene is obtained.
+</li>
 </ul>
@@ Line 230: / Line 232: @@
 {{reflist}}
-=== Further Reading ===
+=== Further reading ===
-* [[Philip Kocienski|Philip J. Kocieński]]: ''Protecting Groups'', 1<sup>st</sup> ed., Georg Thieme Verlag, Stuttgart 1994, ISBN 3-13-135601-4.
+* [[Philip Kocienski|Philip J. Kocieński]]: ''Protecting Groups'', 1st ed., Georg Thieme Verlag, Stuttgart 1994, ISBN 3-13-135601-4.
 * Peter G.M. Wuts, Theodora W. Greene: ''Green's Protective Groups in Organic Synthesis'', 4th Ed., John Wiley & Sons Inc., Hoboken, New Jersey, ISBN 0-471-69754-0.
 * Michael Schelhaas, [[Herbert Waldmann]]: "Schutzgruppenstrategien in der organischen Synthese", in: ''[[Angewandte Chemie]]'', '''1996''', ''103'', pp.&nbsp;2192–2219; [[doi:10.1002/ange.19961081805]] (in German).
@@ Line 238: / Line 240: @@
 === External links ===
-{{Commonscat|Protecting groups}}{{Wikiquote}}
+{{Commons category|Protecting groups}}{{Wikiquote}}
 * [http://www.biocis.u-psud.fr/spip.php?article332 Introduction of protecting group and mechanism of deprotection]
 * [http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem223/protect.pdf Senior undergraduate study notes on this subject, from Prof. Rizzo. ]