UNIT SIX

Reactions of Carbonyl Compounds

Carbonyl compounds are molecules containing the carbonyl

group, C=O. These include:

1
Rxn of C=O
There are some useful reactions of carbonyl compounds involve
carbon hydrogen bonds adjacent to the carbonyl group.
It can be regarded as the backbone of much synthetic organic
chemistry, This is usually result in the replacement of the
hydrogen by some other atom or group, For instance:

2
Addition Reactions
i) Hydration and Hemiacetal Formation
Water adds rapidly to the carbonyl function of RCHO and R2CO
In most cases the resulting hydrate (a geminal-diol) is unstable
relative to the reactants and cannot be isolated.
There is an Exceptions to this reaction,
 one being formaldehyde (a gas in its pure monomeric state).
 Thus, a solution of formaldehyde in water (formalin) is almost
exclusively the hydrate, or polymers of the hydrate.

3
ii) Addition of Alcohols

 In acetal synthesis, since water is formed as a by-product, the

equilibrium can be driven to the right by removing H2O as it is
formed using distillation or other techniques.

 For examples

4
 Formation of Cyclic Hemiacetals

 Cyclic hemiacetals are formed by intramolecular cyclization of

hydroxy aldehydes.
 Examples

 Cyclical Hemiacetal-Acetal Formation

 Cyclic hemiacetals can be converted to acetals by treatment

with an alcohol and acid.
 This converts the OH of the hemiacetal into the OR group of an
5
Example

6
Examples (2)

7
iii) Addition of hydrogen cyanide to C=O

8
iv) The reduction of an RCHO and R2CO

Using lithium tetrahydridoaluminate or sodium,

tetrahydridoborate, same organic product yield.
For example,

9
Another Illustrations:

10
v) Reactions of C=O with Amines

Aldehydes and ketones react with primary amines to form

imines, or Schiff bases.

The mechanism of imine formation involves the nucleophilic

addition of the amine to the carbonyl carbon,
It forms a stable intermediate species called a carbinolamine.
11
Cont’d…,

Carbinolamines are compunds with an

amine group and a hydroxy group
attached to the same carbon;
Are analogous to hemiacetals.

 Mechanism of Carbinolamine Formation

Carbinolamine formation begins with nucleophilic attack on the

carbonyl carbon,
The product of this attack is a neutral, charge-separated
species,
Water and its conjugate acid both play roles in the reaction. 12
Mechanism…,

13
Reaction of C=O With Grignard Reagents

For instance: the reaction between Grignard reagents and

methanal;

14
Reaction between Grignard reagents and
other aldehydes

The reaction between Grignard reagents and ketones

15
Addition-elimination Reactions of C=O
A) Formation of Imines and Related Compounds
The reaction of aldehydes and ketones with ammonia or
1º-amines forms imine derivatives, also known as Schiff bases,
(compounds having a C=N function).

16
B) Wittig Reaction

Phosphorus ylides are easily prepared from triphenyl phosphine

and primary or secondary alkyl halides.
Their preparation involves two reactions;

17
Reaction II…,

Acetals
are functional groups characterized by an sp3-C that is bonded
to two oxygen atoms;
which are themselves attached to a carbon atom.
18
Formation of Acetals

sometimes also known as

ketals, are readily formed from
one molecule of an aldehyde or
ketone and two molecules of an
alcohol under acidic conditions

19
Mechanism of Acetal Formation
Under acidic conditions, R-OH becomes protonated ROH2+.
The hemiacetal OH oxygen abstracts a proton from ROH2+.
Loss of H2O gives a resonance-stabilized alkoxy carbocation.
Nu- attack by the alcohol on the carbocation occurs.
Deprotonation by a further alcohol molecule produces the acetal

20
Ester hydrolysis

Hydrolysis is a chemical process in which a certain molecule is

split into two parts by the addition of a molecule of water.
One fragment of the parent molecule gains a hydrogen ion,
other group collects the remaining hydroxyl group.

Ester is hydrolyzed when treated with excess of water.

This reaction is reverse of ester synthesis from corresponding
carboxylic acid and alcohol.
Reaction is catalyzed by acid or base.

21
Cont’d…,
Both yield same product, except that, in base catalyzed reaction
salt of carboxylic acid is obtained from which acid can be
regenerated by acidic.
Acid catalyzed reaction is reversible; get product in good yields,
it is necessary to use dilute acid and ample amount of water.
Mechanism of ester hydrolysis’ (AAC1 mechanism )
i) Acid catalyzed, unimolecular, acyl oxygen fission

22
For example

Hydrolysis of methyl mesitoate

ii) Acid catalyzed, bimolecular, acyl oxygen fission;

23
iii) Acid catalyzed, unimolecular, alkyl oxygen fission

iv) Acid catalyzed, bimolecular, alkyl oxygen fission

24
A) Base catalyzed, unimolecular, acyl oxygen fission

B) Base catalyzed, bimolecular, acyl oxygen fission

25
C) Base catalyzed, unimolecular, alkyl oxygen fission

D) Base catalyzed, bimolecular, alkyl oxygen fission

26
Examples of ester hydrolysis

27
Acid Chlorides

The functional group of an acid halide is an acyl group bonded

to a halogen.
The most common are the acid chlorides.
To name, change the suffix -ic acid to -yl halide
O O
O O Cl Cl
Cl
RC- CH3 CCl
O
An acyl Ethan oy l ch loride Benzo yl chloride Hexan edio yl ch loride
g roup (Acetyl ch lo ride) (Adip oyl chloride)

Acid chlorides are prepared from carboxylic acids using either

thionyl chloride (SOCl2) or phosphorus pentachloride (PCl5)

28
Reactions of Acid chlorides,

1. Conversion into acids and derivatives:

a) hydrolysis

b) ammonolysis

c) alcoholysis

2. Friedel-Crafts acylation

3. Coupling with lithium dialkylcopper

4. Reduction

29
1) conversion into acids and other derivatives
O H2O O
Hydrolysis
Cl OH
isovaleryl chloride isovaleric acid
3-methylbutanoyl chloride 3-methylbutanoic acid

O NH3 O
Ammonolysis CH3CH2 C CH3CH2 C
Cl NH2
propionyl chloride propionamide
propanoyl chloride propanamide

Alcoholysis O CH3CH2OH O
C C
Cl OCH2CH3
benzoyl chloride ethyl benzoate 30
Schotten-Baumann technique

Ar- acid chlorides are less reactive than aliphatic acid chlorides.
In order to speed up the reactions of aromatic acid chlorides,
bases such as NaOH or pyridine are often added to the reaction
mixture.

O2N O2N
CH3CH2CH2OH O
COCl C
pyridine OCH2CH2CH3
O2N O2N

3,5-dinitrobenzoyl chloride n-propyl-3,5-dinitrobenzoate

31
2) Friedel-Crafts acylation

O AlCl3 O
R C + ArH R C Ar + HCl
Cl
phenone

O AlCl3 O
CH3CH2CH2C Cl + CH3 CH3CH2CH2C CH3 + ortho-

butyryl chloride toluene p-methylbutyrophenone

O AlCl3
CH3CH2CH2C Cl + NO2 No reacton

butyryl chloride

32
3) coupling with lithium dialkylcopper
O O
R C + R'2CuLi R C R'
Cl
ketone

O O
C + (CH3CH2CH2)2CuLi C CH2CH2CH3
Cl

benzoyl chloride lithium di-n-propylcopper butyrophenone

O
O
C +
2CuLi
Cl
isobutyryl chloride lithium diisopropylcopper 2,4-dimethyl-3-pentanone
33
4) Reduction to aldehydes
O LiAlH(t-BuO)3 O
R C R C
Cl H

O LiAlH(t-BuO)3 O
C C
Cl H

mechanism, nucleophilic acyl substitution by hydride :H-

O O
1) R C + :H R C Cl RDS
Cl H

O O
2) R C Cl R C + Cl
H H

34
Acid anhydrides

The functional group of an acid anhydride is two acyl groups

bonded to an oxygen atom.
The anhydride may be symmetrical (two identical acyl
groups) or mixed (two different acyl groups).
To name, replace acid of the parent acid by anhydride.

O O O O
CH3 COCCH3 COC

A cetic an h ydrid e Ben zoic anh ydrid e

Cyclic anhydrides are named from the dicarboxylic acids from

which they are derived.
35
For instance:
O O O

O O O

O O O
Succinic Maleic Phthalic
anhydride anhydride anhydride

Acid anhydrides may be prepared from the condensation

product of two carboxylic acids, with loss of water.
Anhydrides are formed by treatment of carboxylic acids with
strong dehydrating reagents.

36
Cont’d…,
Cyclic anhydrides may be formed by treating a dicarboxylic acid
with another anhydride. For example:

Reactions of Anhydrides,
1) Conversion into carboxylic acids and derivatives.

a) hydrolysis

b) ammonolysis

c) alcoholysis

2) Friedel-Crafts acylation 37
Conversion into carboxylic acids and derivatives

O
COOH
O + H2O
COOH
O
phthalic acid
phthalic anhydride

O O
(CH3CO)2O + NH3 CH3 C + CH3 C
NH2 ONH4
acetic anhydride acetamide ammonium acetate

O O
CH2COCH2CH3
O + CH3CH2OH CH2COH
O
O
succinic anhydride ethyl hydrogen succinate

38
Friedel-Crafts acylation

O O
AlCl3
(RCO)2O + ArH R C Ar + R C
phenone OH

O
AlCl3
(CH3CO)2O + CH3 H3C C CH3 + CH3CO2H
acetic anhydride
toluene p-methylacetophenone

O
AlCl3 O
O + C

O C OH
phthalic anhydride O
o-benzoylbenzoic acid

39
Amides
The functional group of an amide is an acyl group bonded to
a nitrogen atom;
 drop -oic acid from the name of the parent acid and add -
amide. (For the common acid name, drop -ic of the acid name
and add -amide.)
an alkyl or aryl group bonded to the N: name the group and
show its location on nitrogen by N-.

O O H O CH3
CH 3 CNH 2 CH3 C- N H- C-N
CH3 CH3
A cetam ide N- Methy lacetam ide N ,N-D im ethy l-
(a 1° am ide) (a 2° amid e) f orm amid e (DMF)
(a 3° am ide) 40
Chemistry of Amides

Amides are usually prepared by reaction of an acid chloride with

an amine. Ammonia, monosubstituted and disubstituted amines
(but not trisubstituted amines) all react.

.. O
NR3
O NH3 R no reaction
C Cl
3º amine
R C NH2 NHR2
NH2R
1º amide 2º amine
1º amine
O
O
R R C NR2
C NHR
3º amide
2º amide

41
Resonance of Amides:

42
Reaction of Amides

i) Alcoholysis of Amides

Alcoholysis of amides occurs by the same acid catalyzed

mechanism as acid hydrolysis except that the amido group of the
amide is replaced with by an alcohol rather than water.

Dry acid like HCl(g) or H2SO4 must be used;

 otherwise water would compete with the alcohol as the

nucleophile producing some carboxylic acid product in place of
an ester.

The reaction will require a long reflux period because amides

are weak electrophiles and alcohols are weak nucleophiles 43
Possible Illustration 1
OH O
O +
CH3CHCH2CH3 C + NH2(CH3)2
C N(CH3)2
O
H2SO4 CH3CHCH2CH3

N,N-dimethylcyclopentanecarboxamide sec-butyl cyclopentanecarboxylate

ii) Hydride Reduction of Amides

Amides are reduced by LiAlH4 and its product is an amine rather

than an alcohol.
The amide carbonyl group is converted to a methylene group (-
C=O  -CH2). This is unusual
44
This unusual;

iii) Grignard Reduction of Amides

Grignards deprotonate 1º and 2º amides and are not reactive

enough to add to the imide ion product.
N-H protons are acidic enough (pKa = 17) to be abstracted by
.. _
Grignards. : O: :CH3 +MgBr : O:
.. H ..
R C N R C N R
R _ CH :CH3 +MgBr
4
2º amide imide anion

45
iv) Acidic Reaction with H2O - Amides

Hydrolysis of an amide in aqueous acid requires a mole of acid

per mole of amide.
Reaction is driven to completion by the acid-base reaction
between the amine or ammonia and the acid
O O
H2 O + -
N H2 + H2 O + HCl heat
OH + N H4 Cl
Ph Ph
2-Phenylbutanamide 2-Phenylbutanoic acid

Mechanism: Acidic H2O - Amides

Step1: Protonation of the carbonyl oxygen gives a resonance-

stabilized cation intermediate;
46
Mechanism: Acidic H2O - Amides
O +
R C NH2 + H O H
H
+H H H
O O O
+
R C NH2 R C NH2 R C NH2 + H2 O
+
Reso nance-stabil ized catio n i ntermed iate

Step 2: Addition of water (a nucleophile) to the carbonyl carbon

(an electrophile) followed by proton transfer gives a TCAI.
proton
OH OH transfer from OH
+ O to N
R C N H2 + O H R C N H2 R C N H3 +
H O+ O
H H H 47
Step 3: Collapse of the TCAI and proton transfer.
(Elimination
H
O + H
O O
+
R C NH3 + R C + NH3 R C OH + NH 4
OH OH

v) Basic Reaction with H2O – Amides

Hydrolysis of an amide in aqueous base requires a mole of base
per mole of amide and its rxn is driven to completion by the
irreversible formation of the carboxylate salt.
O O
H2 O - +
CH3 CNH + NaOH CH3 CO Na + H2 N
heat
N-Phen yleth anamide Sodiu m A niline
(N-Phen ylacetamid e, acetate
Acetan ilide) 48
Mechanism: Reaction with Basic H2O – Amides

49
Reductions of acid derivative

i) Reduction to Alcohols

LiAlH4 reduces acids, acid chlorides, and esters to primary

alcohols.

ii) Reduction to Aldehydes

Acid chlorides will react with a weaker reducing agent to yield an

aldehyde.

50
iii) Reduction to Amines

LiAlH4 reduces amides and nitriles to amines.

Nitriles and 1 amides reduce to 1 amines.
2 amide reduces to a 2 amine.
 3 amide reduces to a 3 amine.

51
Enolization-Ketonization reactions
 Enols and Enolates

O
E+
O
H Enolate O
E

carbonyl H
O
E+

Enol
52
Base-Catalyzed Enolization: Enolate Anions

Acidity of α-Hydrogen

53
Reactions  to Carbonyl Groups

Carbonyl compounds can undergo reactions at the carbon that

is  to the carbonyl group and reactions proceed by way of
enols and enolates;

The reaction results in the substitution of the E+ for hydrogen.

Carbonyl condensation reactions also occur often in metabolic

pathways.

54
Acidity of α-Hydrogen

55
56
 β-Diketones are much more acidic

 enolate of β-diketone is stabilized; negative charge is

shared by both oxygens.

57
β-Diketones are much more acidic

58
 The Haloform Reaction
Under basic conditions, halogenation of a methyl ketone often
leads to carbon-carbon bond cleavage.
Such cleavage is called the haloform reaction because
chloroform, bromoform, or iodoform is one of the products.

59
The Haloform Reaction

The haloform reaction is sometimes used as a method for

preparing carboxylic acids, but works well only when a single
enolate can form.

60
Mechanism

First stage is substitution of all available a hydrogens by

halogen

61
Mechanism…,

 Formation of the trihalomethyl ketone is followed by its

hydroxide-induced cleavage

62
Alkylations at the α-Carbon

i) Alkylation of Ketones

The synthetic chemistry of enolate anions is centered on their

nucleophilic and basic properties.
Accordingly these ions participate in SN2 reactions with suitable
alkyl compounds.

 In this alkylation, factors to be considered

The basic conditions: enolate ions often lead to side reactions
such as aldol addition and E2 elimination of RX compounds. 63
Factor to be Considered…,

If the alkyl compound reacts with both carbon and oxygen of the
nucleophilic enolate anion
The carbon product is the result of "C-alkylation,"

64
Cont’d…,
Further more, while the aldol reaction involving C-O bond
formation;
is unfavorable (ΔH0 = + 20 kcal mole-l) compared to C-C bond
formation (ΔH0 = -4 kcal mole-l), both O and C-alkylation of the
anion have ΔH0 < 0.

In the alkylation of unsymmetrical ketones, formation of more

than one enolate anion is possible.

65
Cont’d…,
However, when one of the possible enolate anions is especially
stabilized,
either by conjugation or by strong electron-withdrawing groups,
that enolate usually is the dominant form and only one product is
formed and give 2,4-pentanedione is methylated at C3, not at C1 :

For instance: Alkylation of Enamines

ldehydes and ketones react with 2o amines to reversibly form

66
enamines.
Alkylation of Enamine ,

Reversible

67
C-alkylation mechanism

Enamines act as nucleophiles in a fashion similar to enolates.

Because of this enamines can be used as synthetic equivalents
68
as enolates in many reactions.
THREE STEPS…,
i) Formation of the enamine,
ii) Reaction with an eletrophile to form an iminium salt,
iii) Hydrolysis of the iminium salt to reform the aldehyde or ketone
Some of the advantages of using an enamine over and enolate
are enamines are neutral, easier to prepare, and
usually prevent the overreaction problems plagued by enolates.

69
Carbonyl Condensation
Aldol condensation is a self condensation reaction between
molecules containing α-hydrogen atom in presence of base.
The product of reaction is a β-hydroxy carbonyl compound.

The Aldol Reaction

Acetaldehyde reacts in basic solution (NaOEt, NaOH) with
another molecule of acetaldhyde.
The β-hydroxy aldehyde product is aldol (aldehyde + alcohol)
Example...

70
Possible Explaination…,
A basic solution contains comparable amounts
of the aldehyde and its enolate.
Aldehydes undergo nucleophilic addition.
Enolate ions are nucleophiles.

71
Mechanism of Aldol Reactions
Base removes an acidic α-
hydrogen from one one aldehyde
and yield resonance stablized
enolate ion.
The enolate ion attacks a 2nd
aldehyde in a nucleophilic addition
rxn to give a tetrahedral alkoxide ion
intermediate.

Protonation of the alkoxide ion

intermediate yields neutral aldol
product and regenerates the base. 72
Illustration I

Aldol Addition of Acetaldehyde

73
Illustration 2
Aldol Addition of Butanal

74
The Claisen Condensation Reaction

 Reaction of an ester having an -hydrogen with 1 equivalent of

a base to yield a -keto ester;
Self condensation reaction of enolizable ester, in the presence
of base.

75