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REVIEW IN FUNCTIONAL AND PROTECTING GROUPS

NAGHAM MAHMOOD ALJAMALI

Organic Chemistry, Chemistry Department, College of Education, Iraq

ABSTRACT

In organic chemistry, many preparations of delicate organic compounds, some specific parts of their molecules

cannot survive the required reagents or chemical environments. Then, these parts, or groups, must be protected. For

example, lithium aluminum hydride is a highly reactive but useful reagent capable of reducing esters to alcohols. It will

always react with carbonyl groups, and this cannot be discouraged by any means. When a reduction of an ester is required

in the presence of a carbonyl, the attack of the hydride on the carbonyl has to be prevented.

KEYWORDS : Protecting, Function, Carbonyl Protected, Amine Protected

INTRODUCTION

Protecting groups are more commonly used in small-scale laboratory work and initial development than in

industrial production processes because their use adds additional steps and material costs to the process, it 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.

Protecting Groups

• Protecting groups are used in synthesis to temporarily mask the characteristic chemistry of a functional

group because it interferes with another reaction.

• A good protecting group should be easy to put on, easy to remove and in high yielding reactions, and

inert to the conditions of the reaction required.

• For example, consider the following scenario: How can you perform the following reaction?

Figure: 1 The overall transformation required is ester to primary alcohol. This is a reduction of the ester, which requires

LiAlH 4, but that will reduce the ketone as well which we don't want. We can avoid this problem if we "change" the ketone

to a different functional group first. Conceptually, this is like being able to put a cover (shown below) over the ketone

while we do the reduction, then remove the cover.

Journal of Applied, Physical and Bio-ChemistryResearch (JAPBR) Vol. 1, Issue 2, Dec 2015, 75-86 © TJPRC Pvt. Ltd.

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BOC glycine. The tert-Butyloxycarbonyl group is protecting group.

One of the purposes in protecting groups in organic synthesis

the major problems in organic synthesis is the suppression of

accompanied by reaction at other parts of the molecule, especially when more than one functional group is present.

Functional groups usually are the most

one functional group from a reaction occurring at another. Therefore any proposed synthesis must be evaluated at each step

for possible side reactions that may degrade o

an understanding of how variations in structure affect chemical reactivity. Such understanding is acquired through

experience and knowledge of reaction mechanism and reaction ste

To illustrate the purpose and practice of

of cis-2-octene, which we outlined in BUILDING THE CARBON SKELETON

octyn-l-ol. We could write the following:

However, the synthesis as written would fail because the

alkynide anion would react much more rapidly with

from carbon:

The hydroxyl group of 4-bromo

alkynide salt. There are a number of ways to protect hy

on the fact that unsaturated ethers of the type

readily adds to the double bond of such an ether in the presence of an acid catalyst:

Figure: 2 Butyloxycarbonyl group is protecting group.

protecting groups in organic synthesis is to eliminate unwanted side reactions. One of

organic synthesis is the suppression of unwanted side reactions. Frequently the desired reaction is


Functional groups usually are the most reactive sites in the molecule, and it may be difficult or even impossible to insulate


for possible side reactions that may degrade or otherwise modify the structure in an undesired way. To do this will require


experience and knowledge of reaction mechanism and reaction stereochemistry.

To illustrate the purpose and practice of protecting groups in organic synthesis, let us suppose that the synthesis

BUILDING THE CARBON SKELETON, has to be adapted for the synthesis of 5

ol. We could write the following: Stop Wearing Lame Shirts!

Figure: 3

However, the synthesis as written would fail because the alkyne is a weaker acid

alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion

Figure: 4 bromo-l-butanol therefore must be protected before it is allowed to react with the

alkynide salt. There are a number of ways to protect hydroxyl groups, but one method, which is simple and effective, relies

on the fact that unsaturated ethers of the type are very reactive in electrophilic addition reactions

readily adds to the double bond of such an ether in the presence of an acid catalyst:

Figure:5

Nagham Mahmood Aljamali

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is to eliminate unwanted side reactions. One of

unwanted side reactions. Frequently the desired reaction is


reactive sites in the molecule, and it may be difficult or even impossible to insulate


r otherwise modify the structure in an undesired way. To do this will require


, let us suppose that the synthesis

, has to be adapted for the synthesis of 5-

alkyne is a weaker acid than the alcohol, and the

the acidic proton of the alcohol than it would displace bromide ion

butanol therefore must be protected before it is allowed to react with the

droxyl groups, but one method, which is simple and effective, relies

electrophilic addition reactions. An alcohol

Review in Functional and Protecting Groups

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The protected compound is a much weaker acid than the alkyne, and the displacement reaction can

with the alkynide salt without difficulty. To obtain the final product, the protecting group must be removed, and this can be

done in dilute aqueous acid solution by an

Protection of amines:

• Carbobenzyloxy (Cbz) group

• p-Methoxybenzyl carbonyl

• tert-Butyloxycarbonyl

concentrated strong acid (such as HCl or CF

• 9-Fluorenylmethyloxycarbonyl (

by base, such as piperidine

• Acetyl (Ac) group is common in

in adenine nucleic bases and is removed by treatment with a base, most often, with

gaseous ammonia or methylamine. Ac is too stable to be readily removed from aliphatic amides.

• Benzoyl (Bz) group is common in

in adenine nucleic bases and is removed by treatment with a base, most often with

methylamine. Bz is too stable to be readily removed from aliphatic amides.

• Benzyl (Bn) group – Removed by

• Carbamate group – Removed by acid and mild heating.

• p-Methoxybenzyl (PMB)

• 3,4-Dimethoxybenzyl

• p-methoxyphenyl (PMP) group

The protected compound is a much weaker acid than the alkyne, and the displacement reaction can


done in dilute aqueous acid solution by an SN1 type of substitution:

Figure:6 (Cbz) group – Removed by hydrogenolysis

Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by hydrogenolysis

Butyloxycarbonyl (BOC) group (common in solid phase peptide synthesis

concentrated strong acid (such as HCl or CF3COOH), or by heating to >80 °C.

Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis

group is common in oligonucleotide synthesis for protection of N4 in

nucleic bases and is removed by treatment with a base, most often, with

. Ac is too stable to be readily removed from aliphatic amides.

group is common in oligonucleotide synthesis for protection of N4 in

nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or

methylamine. Bz is too stable to be readily removed from aliphatic amides.

Removed by hydrogenolysis

Removed by acid and mild heating.

(PMB) – Removed by hydrogenolysis, more labile than benzyl

Dimethoxybenzyl (DMPM) – Removed by hydrogenolysis, more labile than p

(PMP) group – Removed by ammonium cerium(IV) nitrate

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The protected compound is a much weaker acid than the alkyne, and the displacement reaction can be carried out


hydrogenolysis, more labile than Cbz

solid phase peptide synthesis) – Removed by

solid phase peptide synthesis) – Removed

for protection of N4 in cytosine and N6

nucleic bases and is removed by treatment with a base, most often, with aqueous or

. Ac is too stable to be readily removed from aliphatic amides.

for protection of N4 in cytosine and N6

aqueous or gaseous ammonia or

, more labile than benzyl

, more labile than p-methoxybenzyl

ammonium cerium(IV) nitrate (CAN)

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• Tosyl (Ts) group – Removed by concentrated acid (HBr, H

liquid ammonia or sodium naphthalenide

• Other Sulfonamides (Nosyl & Nps) groups

CARBONYL PROTECTING GROUPS

Protection of Carbonyl Groups:

• Acetals and Ketals – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic

acetals.

• Acylals – Removed by

• Dithianes – Removed by metal salts or oxi

CARBOXYLIC ACID PROTECTING GROUPS

Protection of Carboxylic Acids

• Methyl esters – Removed by acid or base.

• Benzyl esters – Removed by hydrogenolysis.

• tert-Butyl esters – Removed by acid, base and some

• Esters of 2,6-disubstituted phenols (e.g.

butylphenol) – Removed at room temperature by

• Silyl esters – Removed by acid, base and

• Orthoesters – Removed by mild aqueous acid to form ester, which is removed according to ester

properties.

• Oxazoline – Removed by strong hot acid (pH < 1, T > 100

e.g. LiAlH4, organolithium reagents or Grignard (organomagnesium)

Phosphate Protecting Groups:

• 2-cyanoethyl – removed by mild base. The group is widely used in

• Methyl (Me) – removed by strong nucleophiles

Removed by concentrated acid (HBr, H2SO4) & strong reducing agents (

sodium naphthalenide)

(Nosyl & Nps) groups – Removed by samarium iodide,

CARBONYL PROTECTING GROUPS :

Figure: 7 Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic

Removed by Lewis acids.

Removed by metal salts or oxidizing agents.

CARBOXYLIC ACID PROTECTING GROUPS :

Figure: 8 Removed by acid or base.

Removed by hydrogenolysis.

Removed by acid, base and some reductants.

disubstituted phenols (e.g. 2,6-dimethylphenol, 2,6-

Removed at room temperature by DBU-catalyzed methanolysis under high-pressure conditions.

Removed by acid, base and organometallic reagents.

Removed by mild aqueous acid to form ester, which is removed according to ester

Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100

Grignard (organomagnesium) reagents.

removed by mild base. The group is widely used in oligonucleotide synthesis

removed by strong nucleophiles e.c. thiophenole/TEA.


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) & strong reducing agents (sodium in

Removed by samarium iodide, tributyltin hydride[2]

Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic

-diisopropylphenol, 2,6-di-tert-

pressure conditions.[3]

Removed by mild aqueous acid to form ester, which is removed according to ester

°C) or alkali (pH > 12, T > 100 °C), but not

oligonucleotide synthesis.


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Terminal Alkyne Protecting Groups:

• propargyl alcohols in the

• silyl groups, especially in protection of the

ALCOHOL PROTECTING GROUPS

Protection of Alcohols

• Acetyl (Ac) – Removed by acid or base (see

• Benzoyl (Bz) – Removed by acid or base, more stable than Ac group.

• Benzyl (Bn, Bnl) –

chemistry.

• β-Methoxyethoxymethyl ether

• Dimethoxytrityl, [bis-

widely used for protection of 5'-hydroxy group in nucleosides, particularly in

• Methoxymethyl ether

• Methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT)

• p-Methoxybenzyl ether

• Methylthiomethyl ether

• Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl

protecting groups.

• Tetrahydropyranyl (THP)

• Tetrahydrofuran (THF)

• Trityl (triphenylmethyl, Tr)

• Silyl ether (most popular ones include

propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers)

(Tetra-n-butylammonium fluoride, HF-

function in nucleosides, particularly in oligonucleotide synthesis

• Methyl Ethers – Cleavage is by TMSI in DCM or MeCN or Chlorofo

methyl ethers is BBr3 in DCM

alcohols in the Favorskii reaction,

silyl groups, especially in protection of the acetylene itself.[4]

ALCOHOL PROTECTING GROUPS

Figure: 9

Removed by acid or base (see Acetoxy group).

Removed by acid or base, more stable than Ac group.

Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside

Methoxyethoxymethyl ether (MEM) – Removed by acid.

-(4-methoxyphenyl)phenylmethyl] (DMT) – Removed by weak acid. DMT group is

hydroxy group in nucleosides, particularly in oligonucleotide synthesis

Methoxymethyl ether (MOM) – Removed by acid.

methoxyphenyl)diphenylmethyl, MMT) – Removed by acid and hydrogenolysis.

Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation.

Methylthiomethyl ether – Removed by acid.

Removed by acid, base or reductant agents. It is substantially more stable than other acyl

(THP) – Removed by acid.

(THF) - Removed by acid.

(triphenylmethyl, Tr) – Removed by acid and hydrogenolysis.

(most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),

propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or fluoride

-Py, or HF-NEt3)). TBDMS and TOM groups are used for


Cleavage is by TMSI in DCM or MeCN or Chloroform. An alternative method to cleave

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. Bn group is widely used in sugar and nucleoside

Removed by weak acid. DMT group is


ed by acid and hydrogenolysis.

Removed by acid, hydrogenolysis, or oxidation.

Removed by acid, base or reductant agents. It is substantially more stable than other acyl

butyldimethylsilyl (TBDMS), tri-iso-

fluoride ion. (such as NaF, TBAF

)). TBDMS and TOM groups are used for protection of 2'-hydroxy

rm. An alternative method to cleave

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• Ethoxyethyl ethers (EE)

BRIEFLY

Protecting of Alcohol :

• Trimethylsilyl ether (TMS)

• Triethylsilyl ether (TES)

• Triisopropylsilyl ether (TI

• tert-Butyldimethylsilyl ether (TBS, TBDMS)

• tert-Butyldiphenylsilyl ether (TBDPS)

• Acetate (Ac)

• Benzoate (Bz)

• Benzyl ether (Bn)

• 4-Methoxybenzyl ether (PMB)

• 2-Naphthylmethyl ether (Nap)

• Methoxymethyl acetal (MOM)

• 2-Methoxyethoxymethyl ether (MEM)

• Ethoxyethyl acetal (EE)

• Methoxypropyl acetal (MOP)

• Benzyloxymethyl acetal (BOM)

• Tetrahydropyranyl acetal (THP)

• 2,2,2-Trichloroethyl carbonate (Troc)

• Methyl ether

Protecting of Phenol

• Triisopropylsilyl ether (TIPS)

Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N

Figure:10

Trimethylsilyl ether (TMS)

Triethylsilyl ether (TES)

Triisopropylsilyl ether (TIPS)

Butyldimethylsilyl ether (TBS, TBDMS)

Butyldiphenylsilyl ether (TBDPS)

Methoxybenzyl ether (PMB)

Naphthylmethyl ether (Nap)

Methoxymethyl acetal (MOM)

Methoxyethoxymethyl ether (MEM)

al (EE)

Methoxypropyl acetal (MOP)

Benzyloxymethyl acetal (BOM)

pyranyl acetal (THP)

Trichloroethyl carbonate (Troc)

Triisopropylsilyl ether (TIPS)


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Hydrochloric acid[1]

Review in Functional and Protecting Groups 81


• tert-Butyldimethylsilyl ether (TBS, TBDMS)

• Methyl ether

• Benzyl ether (Bn)

• Methoxymethyl acetal (MOM)

• [2-(Trimethylsilyl)ethoxy]methyl acetal (SEM)

Protecting of Amine

• Trifluoroacetamide

• tert-Butoxy carbamate (Boc)

• Benzyloxy carbamate (CBz)

• Acetamide (Ac)

• Formamide

• Methyl carbamate

• 4-Methoxybenzenesulfonamide

• Benzylamine (Bn)

Protecting of Carboxylic Acid

• Methyl ester

• Benzyl ester

Protecting of Aldehyde and Ketone

• Dimethyl acetal

• Ethylene glycol acetal

• Neopentyl glycol acetal

• Trimethylsilyl cyanohydrin

• 1,3-Dithiane

• Diethyl acetal

• 1,3-Dithiolane

Protecting of Sulfonamide


Protecting of 1,2-Diol

• Acetonide

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• Benzaldehyde acetal

• Carbonate

Protecting of Acetylene

• Trimethylsilane (TMS)

Protecting of Indole


• N-(4-Methoxybenzyl)indole (PMB)

• Methoxymethyl aminal (MOM)

General Characteristics

Carbonyl groups are generally protected

basic, nucleophilic, and oxidizing (nonacidic) conditions.

Reaction Mechanism

Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water

system become important to push the reactions to completion.

The order of reactivity for carbonyl compounds is roughly as follows.

Examples

The total synthesis of saxitoxin

Lewis acids or Brønsted acids than sulfurs, the O

Trimethylsilane (TMS)

Butoxy carbamate (Boc)

oxybenzyl)indole (PMB)

Methoxymethyl aminal (MOM)

Carbonyl groups are generally protected as acetals under acidic conditions. Acetals are stable under reductive,

basic, nucleophilic, and oxidizing (nonacidic) conditions.

Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water

system become important to push the reactions to completion.

Figure: 11

The order of reactivity for carbonyl compounds is roughly as follows.

Figure:12

The total synthesis of saxitoxin[1]: Taking advantage of the fact that oxygens are more easily activated by hard

Lewis acids or Brønsted acids than sulfurs, the O-acetal was directly converted into the S-acetal.

Figure: 13


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as acetals under acidic conditions. Acetals are stable under reductive,

Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water from the

more easily activated by hard

acetal.


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The Noyori conditions[2]: Acetals or ketals can be synthesized in high yield using the bis

catalytic TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable

and unreactive that the reverse reaction does not occur, allowing for kinetically

The Otera catalyst[3]: Otera’s distannoxane catalyst mediates acetalization

proposed that the catalyst forms a nucleophilic tin alkoxide as well as acting as a mild Lewis acid. This reaction does not

require any dehydration apparatus.

Ketone-selective acetalization in the presence of aldehyde

dimethylsulfide and TMSOTf, followed by the Noyori conditions.

The protection of cyclohexanone with ethylene glycol.

The most popular acetal protecting groups are shown below. The hydrolysis of six

than that of five-membered ring acetals.

: Acetals or ketals can be synthesized in high yield using the bis

TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable

and unreactive that the reverse reaction does not occur, allowing for kinetically-controlled protection.

Figure: 14 Otera’s distannoxane catalyst mediates acetalization of acid


Figure: 15 selective acetalization in the presence of aldehyde[4]: The example shown here uses treatment with

dimethylsulfide and TMSOTf, followed by the Noyori conditions.

Figure:16 The protection of cyclohexanone with ethylene glycol.[5]

Figure: 17 The most popular acetal protecting groups are shown below. The hydrolysis of six-membered ring acetals is faster

membered ring acetals.

Figure: 18

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: Acetals or ketals can be synthesized in high yield using the bis-TMS ether reagent and

TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable

controlled protection.

of acid-sensitive compounds. It is


: The example shown here uses treatment with

membered ring acetals is faster

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Thioacetals are Deprotected Mainly by

• Methylation then hydrolysis.

• Oxidation (e.g. by hyp

• Hydrolysis using Hg(II).

are Deprotected Mainly by

Methylation then hydrolysis.

Oxidation (e.g. by hypervalent iodine) then hydrolysis.

Hydrolysis using Hg(II).


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REFERENCES

1. Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4

versicolor". FEMS Microbiology Letters

2. Moussa, Ziad; D. Romo (2006). "Mild deprotection of primary N

Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4-dimethoxycinnamyl alcohol and derivatives by Coriolus

FEMS Microbiology Letters 24 (2–3): 225–229. .

Moussa, Ziad; D. Romo (2006). "Mild deprotection of primary N-(p-toluenesufonyl) amides with SmI

85

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dimethoxycinnamyl alcohol and derivatives by Coriolus

toluenesufonyl) amides with SmI2 following

86 Nagham Mahmood Aljamali


trifluoroacetylation". Synlett 2006 (19): 3294–3298. .

3. Romanski, J.; Nowak, P.; Kosinski, K.; Jurczak, J. (Sep 2012). "High-pressure transesterification of sterically

hindered esters". Tetrahedron Lett. 53 (39): 5287–5289..

4. Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2000). Organic Chemistry. Oxford University

Press. p. 1291. .

5. Chan, Weng C.; White, Peter D. (2004). Fmoc Solid Phase Peptide Synthesis. Oxford University Press.

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

7. Merrifield, R. B.; Barany, G.; Cosand, W. L.; Engelhard, M.; Mojsov, S. (1977). "Proceedings of the 5th

American Peptide Symposium". Biochemical Education 7 (4): 93–94.

8. Blanc, Aurélien; Bochet, Christian G. (2007). "Isotope Effects in Photochemistry: Application to Chromatic

Orthogonality". Org. Lett. 9 (14): 2649–2651.

9. Baran, Phil S.; Maimone, Thomas J.; Richter, Jeremy M. (22 March 2007). "Total synthesis of marine natural

products without using protecting groups". Nature (446): 404–408.

10. Daignault, R. A.; Eliel, E. L. Org. Synth. 1973, 5, 303.

11. Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 2818.

12. Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.

13. Nozaki, H. Tetrahedron 1992, 48, 1449.

14. Kim, S.; Kim, Y. G.; Kim, D. Tetrahedron Lett. 1992, 33, 2565.

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