Designing Alcohol

Protecting
Organic Groups

Synthesis-I Carbonyl
Protecting
Learning outcome:
groups • What are protecting groups?
• Why are they necessary?
• How a protecting group should be?
Carboxylic • How to deprotect?
acid • How to add electrophiles to carbonyl
Protecting carbon ( what is umpolung) ?
groups

Amine
Protecting
groups
Subhashri Konar
MSc II Organic Chemistry
Umpolung Seat No: SMOC2122009
Sem IV Paper 2
 Protecting Groups

• Role:
⮚ To temporarily mask the characteristic chemistry of a functional group because it interferes with another reaction.

• Characteristics:
⮚ Introduction should be efficient ⮚ Removal should be easy ⮚ Stable to reaction conditions

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 Explaination

Protecting group is a derivative formed of a functional group that is present in a molecule. It is temporarily attached to
decrease reactivity so that the protected group doesn’t react under the given reaction conditions.
However, minimum two additional synthetic steps are needed to achieve this protection:
The step to form the protected intermediate and a deprotection once the additional selective synthetic steps have been
completed. In addition, the nature of the protective group must be chosen carefully to ensure adequate stability
throughout all the intermediary synthesis steps. Moreover, the conditions for the protection and deprotection steps and
the nature of the protective group itself should not interfere with other functional groups present in the molecule.

Characteristics of a good protecting group:

A good protecting group should be easy to put on, easy to remove and it should be inert to conditions of reaction
required.

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 Protecting Groups of Alcohol

Ethers Esters Acetals/ Ketals Carbonates

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 Explanation

Protection of Alcohols
Protecting groups Deprotection
Methoxyethoxymethyl ethers (MEM) Lewis acids like ZnBr2, TiCl4,
Me2BBr2
Silyl ethers F- (HF, nBu4NF, CsF, KF)
Esters K2CO3, MeOH; KCN, EtOH;NH3,
MeOH
LiOH, THF, H2O
Carbonates HF, CH3CN, Bu4NF, HF•pyridine

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 Silyl Ethers

Example: Protection

Deprotection

Si

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 Explaination
• Protecting groups of alcohols include ethers and esters. Protecting group of diols include
acetals/ketals and carbonates.
• The most common protecting groups for alcohols are the silyl ethers. Here is the idea behind it. We
take a silyl chloride, do a substitution using the alcohol as a nucleophile and then the alcohol
converted into a silyl ether can be used in the presence of any strong base including the Grignard
reagent.
• The reaction with alcohols is carried out in the presence of a base such as triethylamine (TEA) or
Imidazole to deprotonate the oxygen
• The reaction follows SN2 mechanism. We know SN2 reaction requires primary central atom but here
the central atom is tertiary. The point to be noted here is that the central atom is Si and not C.
Silicon being in the third row is larger in size and Si-C bond is longer than C-C bond which reduces
steric effect making SN2 mechanism possible on tertiary atom.
• Silyl ether protecting group is cleavled off by hydrolysis or by using tertbutylammonium fluoride.
Formation of Si-F bond is driving force for fast cleavage.

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 Silyl Ethers

2-bromoethan-1-ol Acetaldehyde Butane-1,3-diol

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 Benzyl ethers

Example:
Protection

a)

b)
Deprotection

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 Explaination

• If we combine 2-bromoethan-1-ol and acetaldehyde we will not get 1,3 diol.

• Because oxygen will donate its lone pair to carbonyl carbon and O-C bond will form but we want C-C
bond formation to occur, so we protect alcohol ysing silyl chloride and carry out the reaction.
• After protection, it is converted to Grignard reagent. The carbon nuclephile of Grignard reagent will
then attack carbonyl carbon and we get the desired product. Deprotection is done to get back the –OH
group.

• Why not use a regular ether instead of a silyl ether?

⮚ It is difficult to cleave off the ether group. Ethers are quite stable.

• Another way to protect alcohol is by converting it into benzyl ether.

• Protection is done using Benzyl halide or Benzyl tricholoroacetamide.
• Deprotection is done by catalytic hydrogenation with H2 over Pd and because of this treatment it is not
suitable for many reactions that involve double or triple bond .

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Protection of 1,2 & 1,3 Diols
Acetals & Ketals of Diols

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 2
3 1
1,2-diol
protection

1,3-diol
protection

⮚ Aldehyde is used to protect 1,3-diols

⮚ Ketones are used to protect 1,2-diols
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 Carbonates of Diols

Propane-1,2-diol Triphosgene 4-methyl-1,3-dioxolan-2-one

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 Explaination

• Diols are protected by converting them into acetal or ketal.

• If aldehyde is used then acetal will be formed and if ketone is used then ketal will be
formed.
• Acetals or ketals of 1,3-diols form 6 membered ring. In acetal there is no 1,3-diaxial
interaction whereas in ketal there is 1,3 diaxial interaction which leads to strain in
ring.
• Therefore acetals are preferred ove ketals to protect 1,3-diols.
• But in case of 1,2 diols ketals can be used because 1,2-diols form 5 membered ring
which takes envelope conformation and is stable.
• In slide 11, there are both 1,2 and 1,3-diols. If aldehyde is used then 1,3-diols are
protected and if ketone is used then 1,2-diols are protected.

• Another way to protect diol is by converting it into carbonate.

• Diphenyl carbonate or Triphosgene is used to protect diols and it is cleaved by acidic
hydrolysis which leads to formation of diol and CO2.

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 Protecting Groups of
Aldehyde & Ketone

Acetal Ketal Thioacetal

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 Explaination

Protecting groups for Aldehyde & Ketone

Protecting groups Deprotection
Acetals mild H3O+
Ketals mild H3O+

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Mechanism of cyclic acetal
formation & clevage

1
2 3

6 5

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 Explaination

We can protect aldehyde and ketone by converting it into either acetals or ketals .
The acetals may be cyclic or acyclic.

Formation of acetals mechanism:

1. The acid catalyst protonates the carbonyl oxygen, making the carbonyl carbon more electrophilic.
2. An alcohol undergoes nucleophilic addition to the carbonyl producing a protonated hemiacetal
3. The OH group of the hemiacetal is protonated making it into a good leaving group.
4. Lone pair electrons on the ether oxygen reforms the C=O bond causing the elimination of water and
producing an oxonium ion.
5. A second alcohol undergoes nucleophilic additon to oxonium ion producing a protonated acetal.
6. Deprotonation occurs.

Acetals hydrolyze to carbonyl compounds under acidic hydrolysis condition.

In hydrolysis, formation of carboxonium ion is the rate determining step. Therefore stability of this ion dictates
hydrolysis rate i.e if it is more stable then hydrolysis rate is faster. More the EDG, more is the hydrolysis rate.

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Protecting Groups of
Aldehyde & Ketone

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 Protecting Group of
Carboxylic acid

Esters

Benzoic acid Diazomethane Methyl benzoate

N,N′-Dicyclohexylcarbodiimide

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 Explaination

Protecting groups for Carboxylic acid

Protecting groups Deprotection
9-Fluorenylmethyl Esters Et2NH, piperidine
Alkyl Esters Bu2SnO, PhH
Benzyl Esters Hydrogenolysis; Na, NH3
Diphenylmethyl Esters mild H3O+, H2, Pd/C, BF3•OEt2

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 Explaination

Carboxylic acids are protected by converting it into esters. There are many esterification reactions. But
in this only esterification using diazomethane and Dicyclohexylcarbodiimide is shown. It is used to
activate carboxylix acid. Deprotection can be done by acid or base hydrolysis.

Diazomethane esterification:
Carboxylic acids react with diazomethane to produce methyl esters. Because of the high reactivity of
diazomethane, it is produced in-situ and then immediately reacted with the carboxylic acid to produce
the methyl ester.
The first step of the mechanism is a simple acid-base reaction to deprotonate the carboxylic acid. The
carboxylate is then the nucleophile of an SN2 reaction with protonated diazomethane to produce the
methyl ester with nitrogen gas as a leaving group

Esterification of carboxylix acid using DCC is Steglich esterification reaction.

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 Protecting Groups of
Amines

Amide Benzyl amines Carbamate

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 Protecting Groups of
Amines
1) Amides:
Mechanism of
Reaction
Deprotection

Glycine
Alanine

Gly-Ala

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 Explaination
• Protection of amines:
• Amines are protected by converting it into Amide, Benzyl amines, and Carbamate.
• Amides:
• Acylation of amines gives amides.
• It is usually done using acyl halide or acid anhydride.
• The reduced reactivity is associated with stabilization produced by the attached carbonyl group because of
its ability to accept electrons from nitrogen atom. This makes nitrogen less nucleophilic than nitrogen
present in amine.
• Amine can be recovered by acid-base hydrolysis.
• Usually amide protection is used in peptide synthesis.
• In the example given,
✔ Amine group in glycine is protected. What if its not protected? Then instead of making bond with alnine it
will react with another glycine molecule.
✔ By converting the carboxyl group of glycine to acyl halide the carbonyl carbon becomes more electrophilic.
Therefore nitrogen of amine of glycine donates its lone pair to more electrophilic carbonyl carbon of glycine.
Self reaction will happen. To prevent this protection is done. Acid hydrolysis is done to deprotect amide.

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 Protecting Groups of
Amines
2) Benzylamines:
Mechanism of
Reaction Protection

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 Protecting Groups of
Amines
3) Carbamates:

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 Protection & Deprotection

Protection Mechanism:

Deprotection Mechanism:

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 Explaination

Protection of Amines
Protecting groups Deprotection
Benzyl (Bn) group hydrogenolysis
Trifluoroacetamides base (K2CO3, MeOH), NH3, MeOH
2,2,2-Trichloroethyl Carbamate zinc dust
9-Fluorenylmethyl Carbamate piperidine, morpholine or
dicyclohexylamine
Benzyl Carbamate Hydrogenolysis, PdCl2, Et3SiH, BBr3

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 Explaination

⮚ Benzyl amine:
• Another way to protect amine is to convert it into benzyl amines.
• N-benzylation happens by reaction of amine with benzyl halide or benzaldehyde.
• Benzyl group is cleaved by Pd-catalyzed hydrogenolysis.

⮚ Carbamate
• There is another way to protect amine, it is to convert it into carbamate.
• Protection by di-tert-butyl dicarbonate ( Boc2O) is called is Boc protection.
• In the example given below we want to carryout reaction on only one amino group so protecting another
amine group is necessary.
• Mechanism involves attack of nitrogen on carbonyl C and forms ammonium subsequent electron shift
leads to formation of CO2, carbamate and t-butyl alcohol. For deprotection, strong acid like trifluoroacetic
acid is used. It involves only protonation and subsequent electron shift.

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 Umpolung

δ+ δ-
Synthetic equivalents of Acyl anion

1,3-Dithiane Methylthiomethyl Cyanohydrin Nitroalkane Enol Ether

sulfoxide

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 Umpolung

1,3-Dithiane

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Corey Seebach reaction

Acetone

3-hydroxy-3-methylbutan-2-one

butane-2,3-dione
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Corey Seebach reaction

3-methyl-3-(pyrrolidin-1-yl)butan-2-one

4-hydroxy-3-methylpentan-2-one

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 Umpolung
Mechanism
Hydrolysis of 1,3-Dithiane

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 Umpolung

Methylthiomethyl sulfoxide

Propan-2-one

Butane-2,3-dione

Acetaldehyde 3-hydroxyl-3-methylbutan-2-one
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 Umpolung
Cyanohydrin Mechanism:

Benzaldehyde
Benzoin
Condensation

Benzoin 37
 Umpolung

Nitroalkane

Nitroethane 3-nitrobutan-2-ol 3-hydroxybutan-2-one

Enol Ether

Acetaldehyde Propan-2-one

Butan-2-one
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 Explaination

• Umpolung or polarity inversion in organic chemistry is the chemical modification of a functional group with the aim
of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that
would otherwise not be possible.
• The concept was introduced by D. Seebach and E.J. Corey. Classic umpolung applications can be found in Grignard
reagents and in the Benzoin condensation.
• Generally the oxygen atom in the carbonyl group is more electronegative than the carbon atom and therefore the
carbonyl group reacts as an electrophile at carbon. This polarity can be reversed when the carbonyl group is
converted into a dithiane or a thioacetal.
• To remove dithiane we use Mercuric chloride in H2O.

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Research Article

DCC

Azulene ester 6-vinyl azulene

An intensely blue-coloured protecting group for carboxylic acids

has been developed.
This indicated that AzulE esters are sensitive to strongly
oxidising and basic agents while being compatible with
reducing conditions and selected other reactions.

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Research Article
It has been demonstrated that dM-Dmoc could serve as a new
protecting group for aliphatic and arylamines. This group could
be removed under nearly neutral oxidative conditions, which
are orthogonal to the commonly used conditions for
deprotection of protected amines including acid, base, and
catalytic hydrogenation. Compared to Dmoc, dM-Dmoc has the
advantage of being stable under a wide range of basic and
nucleophilic conditions.

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 Explaination

• In this research a blue coloured protecting group for carboxylix acids has been developed.
• It has been observed that this group is sensitive to oxidizing and basic reagents.
• But it is compatible with reducing conditions.
• Coloured protecting groups increase reaction efficiency by allowing user to track the protected compound
through all process.
• Another advantage is that colour change will indicate deprotection. Deprotection is achieved using DCC
(dicyclohexylcarbodiimide) in acetonitrile.

• Second research paper is about amine protecting group which is deprotectable under neutral conditions.
• 1,3-Dithiane based dM-Dmoc group was studied for protection of amino group.
• In the previous slide it was seen that Boc group required acid for deprotection. Benzyl group for required catalytic
hydrogenation.
• The dithiane group is cleaved under oxidative condition under which the commonly used Boc, benzyl groups can
survive.
• Compared to Dmoc, dm-Dmoc was found to be more stable under wide range of basic and nucleophilic condition.
• dm-Dmoc stands for dimethyl Dithiane methoxy carbonyl.
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 REFERENCES

• Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation
Stability in Polymeric Nanogels
By Bin Liu and S. Thayumanavan

• An amine protecting group deprotectable under nearly neutral oxidative conditions

By Shahien Shahsavari, Chase McNamara, [...], and Shiyue Fang

• https://www.chemistrysteps.com/protecting-groups-for-alcohols
• https://www.organic-chemistry.org/protectivegroups/
• https://chem.libretexts.org/Bookshelves/Organic_Chemistry/
Organic_Chemistry_Alcohols_and_Phenol_Protection_of_Alcohols
• https://www.masterorganicchemistry.com/2018/06/07/protecting-groups-for-amines-carbamates/
• https://www.fishersci.co.uk/gb/en/scientific-products/lab-reporter-europe/chemicals/amine-
protection-deprotection.html#bocProtection
• www.chem.ucalgary.ca

Thank
You 43