chemistry

1. CHAPTER THREE
Addition, Condensation and
Substitution Reactions of Carbonyl
Compounds
1

2. 2
The key step in carbonyl reaction is the addition of a
nucleophile, which generates a tetracoordinate carbon atom.
Addition occurs when the tetrahedral intermediate goes
directly on to product.
Condensation occurs if the carbonyl oxygen is eliminated and a
double bond is formed.
Substitution results when one of the groups is eliminated from
the tetrahedral intermediate to re-form a carbonyl group.

3. Three possible mechanisms for addition of a nucleophile and a proton to give a
tetrahedral intermediate in a carbonyl addition reaction.
Protonation followed by nucleophilic attack on the protonated
carbonyl group:
Nucleophilic addition at the carbonyl group followed by
protonation
3

4. Concerted proton transfer and nucleophilic attack
Reactivity of Carbonyl Compounds toward Addition
Among the crucial factors are:
structural features of the carbonyl compound;
 the role of protons or other Lewis acids in activating the
carbonyl group toward nucleophilic attack;
4

5. the reactivity of the nucleophilic species and its influence
on subsequent steps; and
the stability of the tetrahedral intermediate and the extent
to which it proceeds to product rather than reverting to
starting material.
There are large differences in the reactivity of the various
carboxylic acid derivatives, such as amides, esters, and acyl
chlorides.
One important factor is the resonance stabilization provided
by the heteroatom substituent, which is in the order N > O
> Cl.
Electron delocalization reduces the electrophilicity of the
carbonyl group
The high reactivity of the acyl chlorides also reflects the
polar electron-withdrawing effect of the chlorine.
5

6. Another factor that strongly affects the reactivity of these carboxylic acid
derivatives is the leaving-group ability of the substituents.
The order of leaving group ability is Cl > OAr > OR > NR2 > O-
6

7. Many carbonyl reactions are carried out under acidic conditions
Protonation or complexation increases the electrophilicity of the
carbonyl group.
Metal cations and other Lewis acids can replace protons as
reagents/catalysts for carbonyl addition reactions.
7

8. Hydration and Addition of Alcohols to Aldehydes and Ketones
8

9. 9

10. 10

11. 11

12. 12

13. 13

14. 14

15. Cyclic Acetals
15

16. 16

17. 17

18. 18

19. 19

20. 20

21. 21

22. 22

23.  Esters react to form tertiary alcohols
O
O
MeMgBr
OH
(after workup with acids)
23

24. 24

25. 25

26. 26

27. 27

28. 28

29. 29

30. 30

31. 31

32. 32

33. 33

34. 34

35. 35

36. Nucleophilic Addition of CN– :
Treatment of an aldehyde or ketone with NaCN and a strong acid such as HCl
adds the elements of HCN across the carbon-oxygen π bond, forming a
cyanohydrin.
36

37. Cannizzaro reaction.
In the presence of concentrated alkali, aldehydes containing no α-hydrogen
undergo self-oxidation and reduction to yield a mixture of an alcohol and a salt of a
carboxylic acid. This reaction is known as the Cannizzaro reaction.
C
H
O
2
strong base
COO-
+ CH2OH
An aldehyde with
no hydrogen
Acid
salt
Alcohol
37

38. Examples:
H C
H
O
2
50% NaOH
room temp.
H COO-
+ CH3OH
Formaldehyde Formate ion Methanol
CHO
Cl
m-Chlorobenzaldehyde
2
50% KOH
COO-
Cl
+
CH2OH
Cl
m-Chlorobenzyl
alcohol
m-Chlorobenzoate
ion
O2N CHO
p-Nitrobenzaldehyde
35% NaOH
O2N CH2OH O2N COO-
Na+
+
Sodium p-nitrobenzoate
p-Nitrophenyl alcohol
2
38

39. Ester Hydrolysis
Esters can be hydrolyzed in either basic or acidic solution
39
Esters with acidic alcohols can be hydrolyzed by using
imidazole as nucleophilic catalyst
Aminolysis of Esters
Esters react with ammonia and amines to give amides

40. In Basic condition, alkoxy elimination occurs while in acidic
condition amine elimination occurs
40
Amide hydrolysis
A) In Basic Media
B) In Acidic Media
The mechanism for acid-catalyzed hydrolysis of amides
involves attack by water on the protonated amide.

41. Acylation of Nucleophilic Oxygen and Nitrogen Groups
The most common O- and N-acylation procedures use acylating agents
that are more reactive than carboxylic acids or their esters. Acyl chlorides
and anhydrides react rapidly with most unhindered alcohols and amines to
give esters and amides, respectively.
41

42. Acylation of alcohols is often performed in the presence of an
organic base such as pyridine.
The base serves two purposes: it neutralizes the protons
generated in the reaction and prevents the development of
high acid concentrations. Pyridine also becomes directly
involved in the reaction as a nucleophilic catalyst
42
The carbodiimides, such as dicyclohexylcarbodiimide, make
up an important group of reagents for converting carboxylic
acids to active acylating agents.

43. 43
Carbonyl Condensation Reactions

44. 44

45. 45

46. 46

47. 47

48. 48

49. 49

50. 50

51. 51
The Dieckmann Reaction
An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters
give good yields of cyclic products.

52. 52
The Dieckmann Reaction

53. 53
The Michael Reaction
The Michael reaction involves two carbonyl components—the enolate of one carbonyl
compound and an ,-unsaturated carbonyl compound.
Recall that ,-unsaturated carbonyl compounds are resonance stabilized and have two
electrophilic sites—the carbonyl carbon and the  carbon.
Carbonyl Condensation Reactions

54. 54
The Michael Reaction
The ,-unsaturated carbonyl component is often called a Michael acceptor.

55. 55
The Michael Reaction

56. 56
The Michael Reaction
• When the product of a Michael reaction is also a -keto ester, it can be hydrolyzed and
decarboxylated by heating in aqueous acid. This forms a 1,5-dicarbonyl compound.
• Recall that 1,5-dicarbonyl compounds are starting materials for intramolecular aldol
reactions.

57. 57
The Robinson Annulation
• The Robinson annulation is a ring-forming reaction that combines a Michael reaction
with an intramolecular aldol reaction.
• The starting materials for a Robinson annulation are an ,-unsaturated carbonyl
compound and an enolate.
Carbonyl Condensation Reactions

58. 58
The Robinson Annulation
• The Robinson annulation forms a six-membered ring and three new C—C bonds—two
 bonds and one  bond.
• The product contains an ,-unsaturated ketone in a cyclohexane ring—that is, a 2-
cyclohexenone.
• To generate the enolate component of the Robinson annulation, ¯OH in H2O or ¯OEt in
EtOH are typically used.

59. 59
The Robinson Annulation
• The mechanism of the Robinson annulation consists of two parts: a
Michael addition to the ,-unsaturated carbonyl compound, followed by
an intramolecular aldol condensation.

60. 60
The Robinson Annulation cont…
• In part two of the mechanism, an intramolecular aldol reaction is followed
by dehydration to form a six-membered ring.

61. 61
The Robinson Annulation cont…
• To draw the product of Robinson annulation without writing out the
entire mechanism each time:
[1] Place the  carbon of the carbonyl compound that becomes the enolate
next to the  carbon of the ,-unsaturated carbonyl compound.
[2] Join the appropriate carbons together as shown. If you follow this method
of drawing the starting materials, the double bond in the product always
ends up in the same position of the six-membered ring.