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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.


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: -


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


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


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,


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.


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


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


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


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+


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


❖ 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


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.


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)


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

protection of functional groups - scifysolutionthe protecting group reagent must react selectively...

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