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TOPIC NAME : ALDEHYDES AND KETONES

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PHARMACEUTICAL ORGANIC CHEMISTRY – 1 SUBJECT CODE (BP202T)

CONTENT:

Structure of Carbonyl Group

Electromeric Effect

Methods of Preparation

General And Named reactions

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• The C-atom is in SP2 hybridized state. Here this c-atom forming 3 sigma bonds

and one pi-bond.

• The pi-bond is generated due to overlap of p-orbital of C-atom with overlap of p-

orbital of O-atom.

• Since it is an SP2 hybridization

• the c-atom and other three bonding atoms lie in same plane.

• Bond angle between three bonds is 120°

• These three bonds adopt trigonal planar geometry.



• The C-atom is in SP2 hybridized state. Here this c-atom forming 3 sigma bonds

and one pi-bond.

• The pi-bond is generated due to overlap of p-orbital of C-atom with overlap of p-

orbital of O-atom.

• Since it is an SP2 hybridization

• the c-atom and other three bonding atoms lie in same plane.

• Bond angle between three bonds is 120°

• These three bonds adopt trigonal planar geometry.



• The carbon-oxygen bond is polar - oxygen is more electronegative than carbon,

so electron density is higher on the oxygen side of the bond and lower on the

carbon side.

• So this forms two points for reaction of carbonyl compounds one C- and O-atom

• Becoz of polarity C-atom is prone to nucleophilic additions attack

• Positive charge (usually a proton hydrogen) attacks the O-atom.



Factors affecting reactivity of Carbonyl compounds towards Nucleophilic Reagents

Carbonyl functional groups characteristic reactions are nucleophililc addition

reactions. Here C-atom in Carbonyl functional groups acts as an electrophile.

Incoming nucleophile is added over structure of carbonyl functional group and

becomes part of it.

Two major factors affecting reactivity are

1. Electronic Factors

2. Steric Factors



Factors affecting reactivity of carbonyl compounds towards Nucleophilic Reagents

• Any factor which will increase the electrophilicity of carbonyl c-atom increases

their reactivity toward nucleophilic addition reaction (it is achieved by electron

withdrawing substitution)

Electronic Factors




• Any factor which decreases the electrophilicity of carbonyl c-atom decreases

their reactivity toward nucleophilic addition reaction (it is achieved by electron

donating substitution)

• Carbonyl compounds aldehydes and Ketones both posses alkyl group which is

an electron donating group and such group decreases the electrophilicity of

carbonyl c-atom thus reactivity of carbonyl group

Electronic Factors




Compare the substitution of carbonyl functional group in aldehydes and ketones,

Aldehyde which contain only one alkyl group where ketones contains two alkyl

groups. Thus Carbonyl C-atom in Aldehydes is more electrophilic and hence

reactive toward nucleophilic addition reaction compared to ketones

Electronic Factors

Only one electron donating group is present in

aldehyde

Two electron donating group is present in

Ketones




Any substitution on carbonyl c-atom makes nucleophile difficult to access the

carbonyl c-atom thus causing steric hindrance.

Steric Factors - aldehydes




Any substitution on carbonyl c-atom makes nucleophile difficult to access the

carbonyl c-atom thus causing steric hindrance.

Steric Factors - ketones




Now compare the structure of aldehydes and ketones,

Aldehyde which contain only one alkyl group (less steric and electronic effect)

where ketones (more steric and electronic effect) contains two alkyl groups. Thus

Aldehydes are more reactive toward nucleophilic addition reaction compared to

ketones

Steric & Electronic Factors



• The carbonyl group is trigonal and in transition state it starts acquiring

tetrahedral configuration in the reactions Thus the attached groups are brought

closer together in transition state during nucleophilic addition reaction

• Thus larger the alkyl substituent greater would be resistance to accommodate

them in the transition state of reaction

• Alkyl group attached to carbonyl carbon releases electrons (+I effect i.e.

inductive effect) and thereby destabilize the transition state by intensifying the

negative charge developing on carbonyl oxygen




• It is defined as complete transfer of pi-electrons either in double bond or triple

bond to one of the bonding atom in presence of attacking reagent

• Since in this effect there is complete transfer of pi-electrons it shows

development of complete positive and negative charge

• This effect is temporary effect and requires presence of attacking agent, effect

vanishes as soon as the reagent is removed

• On the basis of location of adding agent and shifting of pi-electrons there are

two types of electromeric effect

• +E Effect

• -E Effect

Electromeric Effect





METHODS OF PREPARATION OF ALDEHYDES

1) Oxidation of Primary Alcohols

2) Oxidation of Methyl Benzenes

3) Reduction of Acid Chloride

4) Reimer Teimann Reaction (Phenolic Aldehydes)

5) Rosenmunds Reaction



Oxidation :

Loss of Electron & Increase in the oxidation state

Addition of O-atom

Reduction:

Gain of Electron & Decrease in the oxidation state

Addition of H-atom

Oxidizing agent :

An oxidizing agent, or oxidant, gains electrons and is reduced in a chemical

reaction. Also known as the electron acceptor Eg: KMnO4, K2CrO7

Reduicing agent :

A reducing agent, or reductant, loses electrons and is oxidized in a chemical

reaction.



• Primary alcohols undergo oxidation reaction to form corresponding aldehydes .

• Here the oxidizing agents used are

• Potassium Permanganate KMnO4

• Potassium Dichromate K2CrO7

• (Chromium Trioxide CrO3 – H2SO4) Jones Reagent

• PCC (Pyridine Chloro-chromate) Coreys Reagent

• PDC (Pyridine dichromate)

Oxidation of Primary Alcohol



Jones oxidation – oxidation by H2CrO4

Step 1

• This initial step includes reversible formation of chromate ester.

• In this step proton (H+) is removed from alcohol molecule and -OH group is removed

from Chromic acid, both these combines to form Water molecule.

• While Chromic acid and Deprotonated alcohol combines to form chromate ester

• This chromate ester formed is relatively unstable and cant be isolated.




Step 2

• This subsequent step is the slowest step and involves attack of Strong

Base with removal of proton & breakdown of chromate ester into HCrO3

and aldehyde.

• This is elimination step which follows E2 Mechanism



Permanganate oxidation – oxidation by KMnO4

Step 1 Removal of Proton from alcoholic functional group

Step 2 Removal of Hydrogen from alkyl chain of alcohol





2) Oxidation of Methyl Benzenes (Etard Reaction)






2) Oxidation of MethylBenzenes Etard Reaction

The reaction begins with an interaction of allylic hydrogen with chromyl chloride,

forming a precipitate called the Etard complex.

This Etard complex is then decomposed with the help of a reducing environment to

prevent its oxidation into a carboxylic acid.

This reducing environment is generally provided by a saturated solution of aqueous

sodium sulphite.

Carbon tetrachloride is the most commonly used solvent for this method but carbon

disulfide and chloroform can also be used as solvents.




Step 1 Formation of Etard Complex

Here the Proton at Allylic Position is abstracted by chromyl chloride while active

chromium metal reacts with the benzene ring forming precipitate known as etard

complex

Chromyl Chloride –

Used as Oxidizing agent

Carbon Tetrachloride –

Used as Solvent




Step 2 [2,3]-Sigmatropic Rearrangement

A Pericyclic reaction where the end result is that one Sigma bond is changed to

another sigma bond via an uncatalyzed intramolecular process

Reducing conditions provided by saturated aqueous sodium sulphite prevent further

oxidation of the Etard complex into a carboxylic acid






3) Reduction of Acid Chloride (Li-tri Tert-Butoxy Aluminium Hydride)


5) Rosenmunds Reaction (Reduction of Acid Chloride)



Acid chlorides can be converted to aldehydes using lithium tri-tert-butoxyaluminum

hydride (LiAlH(Ot-Bu)3).

The hydride source (LiAlH(Ot-Bu)3) is a weaker reducing agent than lithium aluminum

hydride.

At Initial conditions acid chlorides are highly activated they still react with the

hydride source; however, Later the formed aldehyde will react slowly, which allows

for its isolation.




Mechanism

1) The hydride from Al–H adds to the carbonyl carbon of the acid chloride, breaking

the C–O π bond and forming a tetrahedral intermediate with negatively charged

oxygen .

2) Negatively charged oxygen can re-form the C-O π bond, expelling the chloride ion

(Cl-) along with its bonding electrons in the process called the 1,2-elimination








4) Reimer Teimann Reaction (Preparation of Phenolic Aldehydes)





Treatment of Phenol with Chloroform in the presence of aqueous sodium or

potassium hydroxide followed by hydrolysis of the resulting into formation of

2-hydroxy benzaldehyde (salicylaldhyde) .

This reaction is called Reimer Tiemann reaction.

Single step proceeding through 6 individual events




Step 01 _ Event 01

Chloroform is deprotonated by strong base (normally hydroxide) to form the

chloroform carbanion

Step 01 _ Event 02

Chloroform carbanion is dechlorinated to form the dichlorocarbene




Step 01 _ Event 03

Phenol is deprotonated by strong base (normally hydroxide) to form the phenolate

anion

Step 01 _ Event 04

Attack of the dichlorocarbene from the ortho position gives an intermediate

dichloromethyl substituted phenol




Step 01_ Event 05

Intramolecular deprotonation by carbanionic center

Step 01 _ Event 06

Deprotonatonated substituted phenol will undergo hydrolysis by KOH to form

2-hydroxybenzaldehyde / Salicylic Acid

(Nucleophilic Substitution followed by dehalogenation will occur)



4) Reimer Teimann Reaction Reaction Summary






3) Reduction of Acid Chloride (Li tri-Tert Butoxy Aluminium Hydride)

4) Reimer Teimann Reaction (for preparing Phenolic Aldehydes)

5) Rosenmunds Reaction by (Pd on BaSO4)




• Acid chloride undergoes hydrogenation in the presence of a catalyst such as

Palladium (Pd) on barium sulfate (BaSO4) to form aldehydes.

• The catalyst such as Palladium (Pd) on barium sulfate (BaSO4) also known as

Rosenmund’s Catalyst

• This is also known as Rosenmund’s Reaction.



METHODS OF PREPARATION OF KETONES

1) Oxidation of Secondary Alcohols

2) Fridel Craft Acylation

3) Reaction of Acid Chloride with Organo-copper compound

4) Acetoacetic Ester Synthesis

5) Ozonolysis of Alkenes



Oxidation :

Loss of Electron & Increase in the oxidation state

Addition of O-atom

Reduction:

Gain of Electron & Decrease in the oxidation state

Addition of H-atom

Oxidizing agent :

An oxidizing agent, or oxidant, gains electrons and is reduced in a chemical

reaction. Also known as the electron acceptor Eg: KMnO4, K2CrO7

Reduicing agent :

A reducing agent, or reductant, loses electrons and is oxidized in a chemical

reaction.



• Secondary alcohols undergo oxidation reaction to form corresponding Ketones.

• Here the oxidizing agents used are

• Potassium Permanganate KMnO4

• Potassium Dichromate K2CrO7

• (Chromium Trioxide CrO3 – H2SO4) Jones Reagent

• PCC (Pyridine Chloro-chromate) Coreys Reagent

• PDC (Pyridine dichromate)

Oxidation of Secondary Alcohol




Step 1

• This initial step includes reversible formation of chromate ester.

• In this step proton (H+) is removed from alcohol molecule and -OH group is removed

from Chromic acid, both these combines to form Water molecule.

• While Chromic acid and Deprotonated alcohol combines to form chromate ester

• This chromate ester formed is relatively unstable and cant be isolated.




Step 2

• This subsequent step is the slowest step and involves attack of Strong

Base with removal of proton & breakdown of chromate ester into HCrO3

and Ketone.

• This is elimination step which follows E2 Mechanism



Permanganate oxidation – oxidation by KMnO4

Step 1 Removal of Proton from alcoholic functional group

Step 2 Removal of Hydrogen from alkyl chain of alcohol











Which is Acyl group in chemistry ?

Before proceeding toward acylation of Amines you must know

What is mean by Acylation ?

Which functional groups are source of Acyl group

in chemistry ?

What is the Nature of Acyl groups

C-atom ?

What makes Nature of Acyl group

C-atom Electrophilic ?

Simply the addition of Acyl group

Strongly Electrophilic

Electron withdrawing groups

present on Acyl C-atom



Before proceeding toward acylation of Amines you must know

What is mean by Friedel Craft Alkylation ?

What is mean by Friedel Craft Acylation ?

Both the reactions are example of Electrophilic Aromatic Substitution



2) Friedel Craft Acylation

Step 01 Activation of electrophile occurs by AlCl3

Here the source of electrophile is Acyl Chloride

Initially complex of acyl chloride and aluminium trichloride is generated which loses

AlCl4 forming acylinium ion (the activated electrophile)




Step 02 Addition of electrophile over Nucleophilic Benzene ring

Here the source of nucleophile is Benzene ring, pi-electrons present in the benzene

ring makes it nucleophilic

This step destroys the aromaticity giving the cyclohexadienyl cation intermediate

In this step C-atom bearing Acyl group is in SP3 hybridized state




Step 03 Deprotonation of Benzene Ring and Regeneration of AlCl3

Here Deprotonation of bnezene ring will occur which will restore its aromaticity,

while proton removed from the benzene ring will combine with –Cl forming HCl

This causes regeneration of active catalyst available for further reaction











3) Reaction of Acid Chloride with Organocopper compound

Reaction of Acid Chloride with organocopper compound is an example of

Nucleophilic Substitution reaction , where nucleophile being alkyl / aryl group of

organocopper compound

Acid Chloride do react with grIgnards reagent but froms tertiary alcohol which is

undesirable, such disadvantage is overcomed by use of organocopper compound











Reaction 4: decarboxylation

Reaction 1: Deprotonation forming enolate ion / active nucleophile


Reaction 2: Alkylation by Nucleophilic Substitution Mechanism

Reaction 3: ester hydrolysis











MECHANISM FOR REACTION OF ALKENE OZONOLYSIS

Step 1:

The first step in the mechanism of ozonolysis is the initial electrophilic addition of

ozone to the Carbon-Carbon double bond, which then form the molozonide

intermediate.

Due to the unstable molozonide molecule, it continues further with the reaction and

breaks apart to form a carbonyl and a carbonyl oxide molecule.



MECHANISM FOR REACTION OF ALKENE OZONOLYSIS

Step 2:

The cyclic species called the malozonide rearranges to the ozonide

Step 3:

The cyclic ozonide breaks down into ketones



GENERAL REACTIONS

1) Addition of Hydrogen Cyanide

2) Addition of Sodium Hydrogen Sulphite

3) Addition of Alcohol

4) Addition of Grignards Reagent

5) Oxidation of Aldehydes and Ketones



• Aldehydes and Ketones undergo reaction with Hydrogen Cyanide to produce

compounds known as cyanohydrins

• In these reaction base is used as catalyst to speed up the reaction, since it helps in the

generation of Cyanide ion

• This cyanide ion act as a strong nucleophile and added across the carbonyl functional

group

Addition of Hydrogen Cyanide

cyanohydrins



• This reaction occurs in two steps

1. In step 1 Nucleophilic addition occurs

2. In Step 2 Protonation occurs

Addition of Hydrogen Cyanide



GENERAL REACTIONS








Addition of Addition of Sodium Hydrogen Sulphite

• This reaction occurs in two steps

1. In step 1 Nucleophilic addition occurs

2. In Step 2 Protonation occurs



GENERAL REACTIONS








Organic Chemistry: Electronic Configuration



• Aldehydes undergo addition reaction with

monohydric alcohol, to produce hemiacetals or

alkoxy alcohol intermediate

Addition of Alcohol

• These hemi-acetal undergoes further reaction with

alcohol to produce gem-dialkoxy compound or

acetal

• This reaction is usually carried out in presence of

dry HCl



Addition of Alcohol

This reaction proceeds via following steps

1) Protonation of the carbonyl

2) Nucleophilic attack by the alcohol

3) Deprotonation to by water form

hemiacetal

4) Protonation of the alcohol

5) Removal of water

6) Nucleophilic attack by the alcohol

7) Deprotonation by water to form acetal



Addition of Alcohol

1) 1/2Protonation of the carbonyl

2) 1/2Nucleophilic attack by the alcohol



Addition of Alcohol

3) 1/2Deprotonation from newly added alcohol molecule

4) 2/2Protonation of Alcoholic Functional Group



Addition of Alcohol

5) Removal of Water Molecule

6) 2/2Nucleophilic Attack by alcohole



Addition of Alcohol

7) 2/2Deprotonation by Water Molecule



Addition of Alcohol

This reaction proceeds via following steps

1) Protonation of the carbonyl (1-2)

2) Nucleophilic attack by the alcohol (2-3)

3) Deprotonation to by water form

hemiacetal (3-4)

4) Protonation of the alcohol (4-5)

5) Removal of water (5-6)

6) Nucleophilic attack by the alcohol (6-7)

7) Deprotonation by water to form acetal

(7-8)



GENERAL REACTIONS








Addition of Grignards Reagent

• Grignard Reagents or R-Mg-X demonstrates polar nature.

• In this compound, the carbon atom is electronegative in nature and the Mg atom is

electropositive in nature.

• The polar nature of the Grignard Reagents helps the compound reacts with

aldehydes and ketone to produce additional products.

• The addition products undergo decomposition reaction to give alcohol with water

or dilute sulphuric acid.



Addition of Grignards Reagent



GENERAL REACTIONS








Oxidation of Aldehydes and Ketones



Oxidation of Aldehydes and Ketones

Tollens Reagent Test – Silver Mirror Test



Before beginning to named reactions you should know ?

Aliphatic Aldehydes & Ketones

R- group is any

alkyl group

Aromatic Aldehydes



Before beginning you should know ?

Identify the α-C-atom

Identify the β-C-atom

α-C-atom contains α-H-atom

Identify the β-C-atom contains β-H-atom



NAMED REACTIONS

1) Perkin Reaction

2) Benzoin Condensation

3) Cannizzaro reaction

4) Crossed Cannizzaro Reaction

5) Aldol Condensation

6) Crossed aldol Condensation



Perkin Reaction or Perkin Condensation

• Only Aromatic aldehydes lacking α-Hydrogen atom can undergo perkin reaction

• Most commonly used reaction to synthesize an α,β -unsaturated aromatic acid.

• This reaction involves addition of acid anhydride to aromatic aldehyde in

presence of base (sodium salt of any carboxylic acid) to give α,β -unsaturated

aromatic acid derivatives (eg: Cinnamic acid ).




Mechanism

Step 1 : Formation of Carbanion

Strong base abstracts proton from α-C-atom of acid anhydride to form carbanion




Mechanism

Step 2 : Nucleophilic addition of carbanion over the carbonyl C-atom




Mechanism

Step 3 : Protonation of Carbonyl Oxygen (negatively charged) to form aldol type

product




Mechanism

Step 4 : Aldol product undergo dehydration to form mixed anhydride




Mechanism

Step 5 : Dehydrated aldol product is further hydrolyzed to form α,β-unsaturated acid

How OH- and H- addition governed ?




Mechanism

Step 1: Formation of Carbanion

Step 2: Nucleophilic addition of carbanion over the carbonyl C-atom

Step 3: Protonation of Carbonyl Oxygen (negatively charged) to form aldol type product

Step 4: Aldol product undergo dehydration to form mixed anhydride

Step 5: Dehydrated aldol product is further hydrolyzed to form α,β-unsaturated acid

1

3

5

2

4



NAMED REACTIONS

1) Perkin Reaction








Benzoin Condensation

• Only Aromatic aldehydes lacking α-Hydrogen atom can undergo Benzoin

condensation reaction

• Here two molecules of same aromatic aldehydes undergo condensation in

presence of Potassium cyanide

• This condensation occurs in two steps such as

• In Step 1 Cyanohydrin Carbanion formation occurs

• In step 2 Anion and other aldehyde condenses to form Benzoin



Benzoin Condensation

Step 1

Cyanohydrin Carbanion (Nucleophilic addition of Cyano group followed by 1,2-

proton shift

Step 2

Cyanohydrin reacts with other benzaldehyde molecule forming condensation

product – benzoin (involves 1,2-proton shift followed by elimination of cyano

group)

1 2

2 3a 3b 4



NAMED REACTIONS

1) Perkin Reaction








Cannizzaro Reaction

• This reaction is shown by compounds lacking α-H-atom

• It is self oxidation-reduction system

• In this reaction two molecules of same aldehyde are reacted in presence of conc-

KOH / NaOH together to produce carboxylic acid, primary alcohol.

• It involves following steps

• 1) Nucleophilic addition of (Hydroxyl) OH- group in first aldehyde molecule

• 2) Intermolecular Hydride Transfer to second aldehyde molecule

• 3) Addition of proton in second aldehyde molecule



Cannizzaro Reaction – self oxidizing reducing system

Meachnism

Step 1: nucleophilic addition of (Hydroxyl) OH- group in first aldehyde molecule

Step 2: Intermolecular Hydride Transfer to second aldehyde molecule

Step 3: Proton addition in second aldehyde molecule

One molecule is oxidized (addition of O-atom)

and one molecule is reduced (Addition of H2

across the double bond)



Cannizzaro Reaction




• 3) Addition o f proton in second aldehyde molecule

• One molecule is oxidized (addition of O-atom) and one molecule is reduced

(Addition of H2 across the double bond)

• Therefor the net reaction is



NAMED REACTIONS

1) Perkin Reaction








Crossed Cannizzaro Reaction

• This reaction is shown by compounds lacking α-H-atom

• It is self oxidation-reduction system

• In this reaction two different molecules aldehyde are reacted in presence of conc-

KOH / NaOH together to produce mixture of carboxylic acid, primary alcohol.




• 3) Addition o f proton in second aldehyde molecule



Crossed Cannizzaro Reaction

• In this reaction Benzaldehyde and formaldehyde are reacted together forming

Benzyl alcohol and Formic acid as the main product

• Application of Crossed Cannizzaro reaction

• 1) Synthesis of benzyl alcohol from Benzaldehyde and formic acid

• 2) Synthesis of o-methoxy benzyl alcohol from o-methoxy Benzaldehyde and

formic acid



NAMED REACTIONS

1) Perkin Reaction








Aldol Condensation reaction

• This reaction is shown by compounds having α-H-atom

• In this reaction two different molecules aldehyde/ ketones are reacted together

in presence of dilute acid or base forming Aldol (Aldehyde + alcohol) as product. It

involves following steps

• 1) Removal of α-proton from carbonyl compound by the strong base and

formation of carbanion

• 2) carbanion reacts with other carbonyl compound molecule to yield anionic

intermediate

• 3) Anionic intermediate abstracts the proton from water molecule forming

aldol product



Aldol Condensation

Meachnism

Step 1: Removal of α-proton from carbonyl compound by the strong base and formation of carbanion

Step 2: carbanion reacts with other carbonyl compound molecule to yield anionic intermediate

Step 3: Anionic intermediate abstracts the proton from water molecule forming aldol product



NAMED REACTIONS

1) Perkin Reaction








Crossed Aldol Condensation

Meachnism

Step 1: Removal of α-proton from carbonyl compound by the strong base and formation of carbocation

Step 2: carbocation reacts with other carbonyl compound molecule to yield anionic intermediate

Step 3: Anionic intermediate abstracts the proton from water molecule forming aldol product



Crossed Aldol Condensation

Meachnism

Step 4: Removal of proton forming enolate ion

Step 5: Enolate ion looses hydroxide ion



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