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 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.
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 • Triethylsilyl (TES) — 10–100× stabler than a TMS group. Cleaved with trifluoroacetic acid in water/
tetrahydrofuran, acetic acid in water/tetrahydrofuran, or
hydrogen fluoride in water or pyridine •
tert-Butyldimethylsilyl (TBDMS or TBS) — Cleaved with acetic acid in tetrahydrofuran/water, Pyridinium tosylate in methanol, trifluoroacetic acid in water, hydrofluoric acid in
acetonitrile, pyridinium fluoride in tetrahydrofuran,
tetrabutylammonium fluoride in THF. Commonly protects 2'-hydroxy function in
oligonucleotide synthesis. • Triisopropylsilyl (TIPS) — Similar conditions to TBS but longer reaction times. •
tertButyldiphenylsilyl (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. Bn group is widely used in sugar and nucleoside chemistry. •
Trityl (triphenylmethyl, Tr) — Removed by acid and hydrogenolysis •
p-Methoxybenzyl (PMB) — Removed by acid, hydrogenolysis, or oxidation – commonly with
DDQ. •
p,
mDimethoxybenzyl — Removed via oxidation with DDQ or ceric ammonium chloride 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, but also admits reductive removal: sodium in liquid ammonia, catalytic hydrogenation (palladium hydroxide on activated carbon), or Raney nickel in ethanol • Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N
hydrochloric acid •
Methoxyethoxymethyl ether (MEM) — Removed by hydrobromic acid in tetrahydrofuran or
zinc bromide in dichloromethane •
Methoxymethyl ether (MOM) — Removed by 6 M hydrochloric acid in tetrahydrofuran/water •
Tetrahydropyranyl (THP) — Removed by acetic acid in tetrahydrofuran/water,
ptoluenesulfonic acid in methanol •
Methylthiomethyl ether — Removed by acid or
soft metal oxidants: base-buffered
mercuric chloride in wet acetonitrile or
silver nitrate in wet tetrahydrofuran • 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, concentrated hydrofluoric acid in acetonitrile, or
tetrabutylammonium fluoride in HMPT (
Hexamethyl phosphoric acid triamide) or in tetrahydrofuran Other ethers: •
p-Methoxyphenyl ether (PMP) – Removed by oxidation. •
Tert-butyl ethers (tBu) – Removed with anhydrous trifluoroacetic acid,
hydrogen bromide in acetic acid, or 4 N hydrochloric acid •
Allyl — Removed with potassium
tertbutoxide
DABCO in methanol, palladium on activated carbon, or diverse platinum complexes – conjoined with acid workup. • Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM. See •
Tetrahydrofuran (THF) – Removed by acid.
1,2-Diols The 1,2diols (
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.
Amine protecting groups . The
tert-butyloxycarbonyl group is marked
blue.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.
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, and the trifluoroacetamides, which hydrolyze easily in base.
Indoles,
pyrroles und
imidazoles — verily any aza-heterocycle — admit protection as
Nsulfonylamides,which are far too stable with aliphatic amines.
Nbenzylated 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: •
Carbobenzyloxy (Cbz) group — Removed by
hydrogenolysis:
hydrogen and
palladium on
activated carbon, or lithium or sodium in liquid ammonia. •
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 or CF3COOH), 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) or
N-Methyl-2-pyrrolidone, or 50%
morpholine in DMF for sensitive
glycopeptides. Common in
solid phase peptide synthesis •
Allyloxycarbonyl group — Removed with complexes of metals like palladium(0) or
nickel(0). Other amides: •
Acetyl (),
Benzoyl () 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 (trichloroethoxycarbonyl) 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 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 1,2hydroxythiols or dithioglycols – the so-called
O,
S– or
S,
S-acetals. Overall,
transacetalization 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 acetalization. Modern variants also use glycols, but with the hydroxyl hydrogens replaced with a trimethylsilyl group. 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 or
iron(III) chloride on
silica gel can be performed with workup in chloroform. 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. 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 equilibrium lies on the side of the acetal. In contradistinction to the
O,
Oacetal case, it is not needed to remove water from the reaction mixture in order to shift the equilibrium.
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. 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.
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. 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 or
pig liver esterase. Can be formed from diazomethane in
diethyl ether,
caesium carbonate and methyl iodide in
N,
Ndimethylformamide, or methanol and catalytic trimethylsilyl chloride •
Benzyl esters — Also removed by hydrogenolysis. •
Benzhydryl esters — Same as benzyl, but easier to cleave •
tert-Butyl esters – Also removed by acid and some reductants. Can be formed from
carboalkoxylation using isobutene in dioxane and catalytic sulfuric acid or under mild conditions via their
silver carboxylate using
tert-butyl iodide • 2,6Dialkylphenols (e.g.
2,6-dimethylphenol,
2,6-diisopropylphenol,
2,6-di-tert-butylphenol) — Also removed in
DBU-catalyzed high-pressure methanolysis at room temperature. • Allyl esters — As with allyl ethers, also removed by diverse platinum complexes – connected with acid workup •
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 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
trans1,2dibromoalkane: the regeneration of the alkene then follows with preservation of conformation via elemental
zinc or with
titanocene dichloride. • 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.
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. Cleavage follows hydrolytically – with potassium carbonate in methanol – or with fluoride ions like for example with
tetrabutylammonium fluoride. 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.
Other Photolabile protecting groups As a
proof of concept orthogonal deprotection is demonstrated in a
photochemical transesterification by
trimethylsilyldiazomethane utilizing the
kinetic isotope effect: 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==