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PROTECTION OF FUNCTIONAL GROUPS
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Protecting groups for amines, alcohols, aldehyde and ketones The presence of several functional groups in a molecule can greatly complicate
the synthetic design if reagent does not discriminate with various functional
groups. Example if a molecule has ketone and carboxylic acid group and if we
reduce with Lithium aluminium hydride both the groups will reduce, therefore
we need to protect ketone first.
A protecting group must fulfil a number of requirements:
1. The protecting group reagent must react selectively in good yield to give a
protected substrate which must stable to the projected reaction condition.
2. The protecting group must be selectively removed in good yield by readily
available reagents preferably under mild conditions.
3. The protecting group should not have additional functionality that might
provide additional sites of reaction. Introduction of a protective group adds
additional steps to a synthetic scheme.
Hence, one should limit the use of protecting groups to a minimum and avoid
them if possible.
❖ Protection of amino (NH) groups Primary and secondary amines are prone to oxidation and N-H bonds undergo
metalation on exposure to organolithium and Grignard reagents. The amino
group can also protonate or reacts with electrophiles (R-X).
To make the amine less reactive, it can be converted into an amide via acylation.
Protection of the amino group in amino acids plays an important role in peptide
synthesis.
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1. N-Benzyl groups (N-Bn) They are useful for replacing the N-H protons in primary and secondary amines
when exposed to organometallic reagents or metal hydrides. Depending on the
reaction conditions, primary amines can form mono or dibenzylated products.
They are stable to Lewis acids and can be removed by Hydrogenolysis with Pd
catalysts and hydrogen gas.
.
BnBr,TEA MeCN
Pd/C, H2
Pd/C, H2BnBr,NaH THF
Selectively Hydrogenation of N-benzyl amine can be achieved in presence of
benzyl ethers using Pd(OH)2/C.
EtOH
Pd(OH)2/C,
H2, 50 Psi
2. Amides: -
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Acylation of primary and secondary amines with acetic anhydride or acid
chlorides results in corresponding amides in which the basicity of the nitrogen
is reduced, making them less susceptible to attack by electrophilic reagents.
Amine can be regenerated by acid catalysed hydrolysis.
H+,H2O
(Ac)2O
OR
Ac-Cl
Benzamides (N-Bz) are formed by the reaction of amines with benzoyl chloride
in presence of bases like pyridine or trimethylamine. The group is stable to
pH 1-14, nucleophiles, organometallics (except organolithium reagents),
catalytic hydrogenation and oxidation.
It is removed by strong acids (6N HCl, HBr) or diisobutylaluminum hydride.
3. Carbamates
Reaction of primary and secondary amines with methyl or ethyl chloroformate
in the presence of a tertiary-amine furnishes the corresponding methyl and ethyl
carbamates, respectively. The protected amines behave like amides therefore
they no longer act as nucleophiles.
They are stable to oxidizing agents and aqueous bases but can react with
reducing agents. Iodotrimethylsilane is often use for the removal of the N-
methoxycarbonyl groups
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TEA or K2CO3
R'= Me, Et
Me3SiI
CHCl3
The benzyloxy carbonyl group (Cbz or Z) is one of the important nitrogen-
protecting groups in organic synthesis. It is synthesized by reacting the amine
with benzyloxy carbonyl chloride in the presence of a tertiary-amine. The
protected amine is stable to both acids and bases and can be removed by
dissolving metal reduction (LiO, liq. NH3), catalytic hydrogenation (Pd/C, H2),
triethyl silane and palladium chloride.
TEA,DCM
Pd/C, H2
The t-butoxycarbonyl group (Boc) is another widely used protecting group for
Primary and secondary amine. It stable to hydrogenolysis and resistant to bases
and nucleophilic reagents but is more prone to cleavage by acids than the Cbz
group.
Deprotection of the N-Boc group is conveniently carried out with CF3COOH or 4
N HCl in dioxane. Selective cleavage of the N-Boc group in the presence of other
protecting groups is possible using AlCl3
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BOC anhydride
TEA,DCM
tBu-OH CO2
HClorCF3COOH
CO2
BOC anhydride=
❖ Protection of alcohols (OH) groups The most important protecting groups for alcohols are ethers and mixed acetals.
The proper choice of the protecting group is crucial if chemo selectivity is
desired.
Reactivity of alcohols: l° > 2° > 3° ROH
The stability of ethers and mixed acetals as protecting groups for alcohols varies
from the very stable methyl ether to the highly acid-labile trityl ether. However,
all ethers are stable to basic reaction conditions. Hence, ether or mixed acetal
protecting groups specifically tolerate, RMgX and RLi reagents.
Nucleophilic reducing reagents such as LiAlH4 and NaBH4, Oxidizing agents such
as CrO3, 2 pyridine, pyridinium chlorochromate (PCC) and MnO2,
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1. Alkyl ethers Methyl ether Methyl ethers are prepared using Williamson ether synthesis. For sterically
hindered alcohols, the methylation should be done in KOH/DMSO.
Reagents used for cleaving methyl ethers are Me3SiI or BBr3 Tert-Butyl Ethers t-Butyl ethers are prepared by reacting alcohol with t-butanol or alkene under acidic condition
tBuOH
or
H2SO4 or
BF3.OEt
4 N HCl
They are stable to nucleophiles, hydrolysis under basic conditions,
organometallic reagents, metal hydrides, and mild oxidations.
They are cleaved or removed by dilute acids.
Benzyl Ethers
Benzyl ethers are quite stable under both acidic and basic conditions and toward
a wide variety of oxidizing and reducing reagents. Therefore, they are frequently
used in organic syntheses as protecting groups.
They are removed by hydrogenation in presence of Pd/C, Raney Nickel or with
sodium in ammonia.
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NaH,THFPhCH2Br
Pd/C,H2,EtOH
Or
Ra-Ni,EtOH
Or
Na,NH3,EtOH p-Methoxybenzyl Ethers (PMB) The PMB ether is less stable to acids than benzyl ether.
It can be removed oxidatively with DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone) under conditions that do not affect protecting groups such as
acetals, RO-Bn (or RO-BOM), RO-MOM, RO-MEM, RO-THP, RO-TBS, benzoyl,
tosyl, or acetate and ceric ammonium nitrate.
PMB-Cl,N(Et)3
DMAP
DDQ, DCM H2O
Triphenylmethyl Ethers (Trityl ether) Trityl ethers are stable to bases and nucleophiles but are readily cleaved by acids
or by hydrogenolysis (Pd, H2). The trityl group may be selectively cleaved in the
presence of tert-butyldimethylsilyl, triethylsilyl, or benzoyl (Bz) groups
PPh3Cl
N(Et)3,DCM
DMAP
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HCO2H, H2O
2. Silyl ethers The popularity of silicon protecting groups stems from the fact that they are
readily introduced and removed under mild condition. Moreover, a wide variety
of silylating agents are available for tailor-made protection of ROH groups.
The chemo selectivity of silylating agents for alcohols and the stability of the
resultant silyl ethers toward acid and base hydrolysis, organometallic reagents,
and oxidizing and reducing agents increases with increased steric size of the
groups attached to silicon.
Bases generally employed for the preparation of silyl ethers include R3N,
imidazole, DMAP, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).
Hindered ROH groups are best converted to the corresponding alkoxides with
NaH, MeLi or n-BuLi prior to silylation.
R3Si-Cl
BasenBu4N
+F-
THF
Depending on the structure of silyl ethers, they can be deprotected by aqueous
acids, and fluoride salts such as n-Bu4N+F-, which is soluble in organic solvents
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Trimethylsilyl Ethers (TMS)
Me3Si-Cl
N(Et)3
THF
They are prepared by reacting alcohols with TMS chloride in presence of Triethyl
amine.
They are very susceptible to solvolysis in protic media either in the presence of
acids or bases. Cleavage of RO-TMS occurs on treatment with citric acid in
CH3OH at 20°C (10 min)
Triethylsilyl Ethers (TES)
Et3Si-OTf
2,6 lutidine DCM
Triethylsilyl ethers have been used as protective groups in Grignard additions,
Swern and Dess-Martin oxidations, Wittig reactions, metallations with R3NLi
reagents.
They are cleaved with DDQ.
t-Butyldimethylsilyl Ethers
tBuMe2Si-Cl
ImidazoleDMAP, DMF
nBu4N+F-
THF
tBuMe2Si-OTf
2,6 lutidine
Or
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The t-butyldimethylsilyl group is the most widely used of the silicon protecting
groups.
The rate of silylation of alcohols with TBSCl follows the trend: 1° ROH >
2° ROH > 3° ROH. The large difference in rate of silylation between primary and
secondary OH groups makes the TBSCl reagent well suited for the selective
protection
For protecting a primary OH group in the presence of a secondary OH group, one
should use TBS-Cl and Et3N with DMAP as a catalyst. Hindered 2° and 3° alcohols
can be silylated with t-BuMe2SiOTf and 2, 6-lutidine as a base.
Triisopropylsilyl Ethers(TIPS) Triisopropylsilyl chloride (TIPS-CI) is an excellent reagent for the selective
protection of a primary OH in the presence of a secondary OH.
A simple method for silylation of alcohols and phenols is using TIPS-C1 and
imidazole.
TIPS group is stable under a wide range of reaction conditions, such as acid and
basic hydrolysis, and toward powerful nucleophiles.
i-Pr3Si-Cl
Imidazole
nBu4N+F-
THF
DMAP, DCM Tetrahydropyranyl Ethers(THP)
TsOH -H+
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The THP group is readily introduced by reaction of dihydropyran with an alcohol
in the presence of an acid catalyst such as TsOH, BF3OEt, or POCl3. For sensitive
alcohols such as allylic alcohols PPTS (pyridinium p-toluene sulfonate) can be
used
The THP group is readily hydrolysed under aqueous acidic conditions with AcOH-
THF, TsOH, PPTS-EtOH, or Dowex-H
Methoxymethyl Ethers (MOM) Alpha-Halo ethers are often used for the protection of alcohols.
The reaction of chloromethyl methyl ether (MOM-CI, a carcinogen) with an
alkoxide or with an alcohol in the presence of i-Pr2NEt (Hunig's base) furnishes
the corresponding formaldehyde acetal.
Alkylation of 3°-alcohols requires the more reactive MOM-I, derived from MOM-
C1 and NaI in the presence of DIPEA.
Cleavage of the MOM group with dilute acids or with PPTS in t-BuOH
regenerates the alcohol.
A mild and selective reagent for removing the MOM group in the presence of
methyl or benzyl ethers, -SiPh2t-Bu ethers, or esters is brornotrimethylsilane.
R3SiBr
DCM,-30°CMol. sieves
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❖ Carboxylic Acid Esters The use of carboxylic acid esters as protective groups for alcohols is limited as
they undergo acyl substitution, hydrolysis or reduction. Reagents used for the
preparation of esters in the presence of Et3N or pyridine are Ac2O, PhCOCl,
(PhCO)2O, and t-BuCOCl (pivaloyl chloride).
Deprotection of esters is usually done under basic condition.
❖ Protection of Diols as acetal 1, 2- and 1,3-diols can be protected as acetals or ketals by reacting with ketones
or aldehydes in the presence of an acid catalyst. Once they are formed, acetals
are very stable to basic conditions but are labile toward acids.
Acetal protection allows the selective blocking of pairs of OH groups in
polyhydroxy compounds.
Only vicinal cis-OH groups of cyclic 1,2-diols readily form acetals. Acetals
exchange is the most common method for preparing isopropylidene acetals
Me2CO,H2SO4
Or
Me2C(OMe)2,
TsOHIsopropylidene derivative Acetonide
Isopropylidene acetal formation in the acyclic 1,2,4-butanetriol D again favours
the five-member 1,3-dioxolane ring even if one of the OH groups is tertiary
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Me2CO
PPTS, CuSO4
Acetalization of D-mannitol (E) with acetone leads to the preferential blocking
of the two terminal 1,2-diol moieties
Me2C(OMe)2
Sn(Cl)2, DME
Both cis- and trans-1,3-diols form cyclic acetals with aldehydes in the presence
of an acid catalyst to furnish the corresponding benzylidene and ethylidene
derivatives respectively.
Ph-CHO
ZnCl2
Benzylidene derivative Acetonide
❖ Protection of aldehydes and Ketones Acyclic and cyclic acetals are the most important carbonyl protecting groups of
aldehydes and ketones and also serve as efficient chiral auxiliaries for the
synthesis of enantiomerically pure compound.
The acetal protective group is introduced by treating the carbonyl compound
within alcohol, an ortho ester, or a diol in the presence of a Lewis acid catalyst.
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Acetalization with Trialkyl Orthoforrnates. In an acetal exchange reaction,
trialkyl orthoformates will convert carbonyl groups to their corresponding acetal
derivatives without concomitant formation of water. Weak acids such as
amberlyst- 15 (a sulfonic acid resin) catalyse the acetalization.
CH(OEt)3
Amberlyst-15
Acetalization with Diols. 1, 3-Dioxolane (five-member ring acetal) is the most
widely used C=O protecting group. The formation of acetals with diols provides
an entropic advantage over the use of two equivalents of an alcohol. The water
formed is removed by azeotropic distillation.
HO(CH2)2(OH)
H+
H2O
Acid-catalysed acetalization of α-β unsaturated ketones may result in double
bond migration. The extent of migration of the double bond of enones depends
on the strength of the acid catalyst.
HO(CH2)2(OH)
TsOH(-H2O)
K. Noyori developed a procedure that avoids migration of the double bond
during acetalization of unsaturated ketones (enones)
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TMSO(CH2)2(OTMS)
TMSOTfDCM,-78°C
The presence of a double bond in enones increases the electron density at the
carbony1carbon, thereby reducing its reactivity toward acetalization
HO(CH2)2(OH)
TsOH, Toluene -H2O
The preparation of thioacetals involves treatment of the carbonyl substrate with
a dithiol in the presence of an acid catalyst, usually TsOH or BF3.OEt,. Since
thioacetals are quite stable toward hydrolysis, there is no special need to
remove the H2O formed during the reaction. Also, since it is more difficult to
equilibrate thioacetals than acetals via protonation, double bond migration in
thioacetalization of enones is usually not observed.
HS(CH2)2(SH)
TsOH(-H2O)
The lower basicity of RS-H as compared to RO-H makes thionium
ion formation more difficult and thus renders thioacetals more resistant to
hydrolytic cleavage. Hence an O-acetal moiety can be selectively deprotected
in the presence of a thioacetal protecting group.
50% CF3COOH
CHCl3
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