Aldehydes and Ketones II.

NUCLEOPHILIC
ADDITIONS TO THE CARBONYL GROUP

OBJECTIVES
1. Describe the reactivity of carbonyl group towards the nucleophilic
addition (PAGE : 741)
2. Predict the products of cyanohydrin from synthesis of -hydroxy acids
and hydrolysis of nitriles (PAGE : 755)
3. Predict the products from the addition of Organometallic Reagents
Grignard and alkyl lithium reagents) to aldehydes and ketones. (PAGE
: 566-568, 776)
4. Predict the products from the addition of water (hydration) to aldehydes
and ketones (PAGE : 746)
5.. Predict the products of acetals and hemiacetal from the addition of
Alcohols and describe the formation of cyclic acetals (PAGE : 748) and
its uses as protecting group. (PAGE : 749)
6. Predict the products from the addition of amines to aldehydes and
ketones which produce Imines from 1o Amines (PAGE : 751), Enamines
from 2o Amines (PAGE : 754), Enamines for Alkylation of Ketones
(PAGE : 755)
7. Predict the products from Wittig Reaction (PAGE : 757-760)

1. Describe the reactivity of carbonyl group towards the

nucleophilic addition (PAGE : 741)

Chapter 16

 Nucleophilic Addition to the Carbonyl

Groups
o Addition of a nucleophile to a carbonyl carbon occurs because
of the d+ charge at the carbon

o Addition of strong nucleophiles such as hydride or Grignard

reagents result in formation of a tetrahedral alkoxide
intermediate
H The carbonyl p electrons shift to oxygen to give the alkoxide
H The carbonyl carbon changes from trigonal planar to tetrahedral

Chapter 16

Chapter 16

o acid catalyst is used to facilitate reaction of weak nucleophiles

with carbonyl groups
Protonating the carbonyl oxygen enhances the electrophilicity of the carbon

REACTIVITY OF ALDEHYDE AND

KETONE

Chapter 16

 Relative Reactivity: Aldehydes versus Ketones

o Aldehydes are generally more reactive than ketones
The tetrahedral carbon resulting from addition to an aldehyde is less

sterically hindered than the tetrahedral carbon resulting from addition

to a ketone
Aldehyde carbonyl groups are more electron deficient because they
have only one electron-donating group attached to the carbonyl
carbon

Chapter 16

2. Predict the products of cyanohydrin from synthesis of

-hydroxy acids and hydrolysis of nitriles (PAGE :
755)

Chapter 16

 The Addition of Hydrogen Cyanide (PAGE : 755)

Aldehydes and ketone react with HCN to form a

cyanohydrin
A catalytic amount of cyanide helps to speed
the reaction

Chapter 16

10

The cyano group can be hydrolyzed or reduced

Hydrolysis of a cyanohydrin produces an ahydroxycarboxylic acid (Sec. 18.8H)

Chapter 16

11

 Reduction of a cyanohydrin produces b-

aminoalcohol

Chapter 16

12

3. Predict the products from the addition of

Organometallic Reagents Grignard and alkyl lithium
reagents) to aldehydes and ketones. (PAGE : 566568, 776)

Chapter 16

13

 Reaction of Grignard Reagents with Carbonyl Compounds

Nucleophilic attack of Grignard reagents at carbonyl carbons is the
most important reaction of Grignard reagents
Reaction of Grignard reagents with aldehydes and ketones

yields a new carbon-carbon bond and an alcohol

Chapter 12

14

Chapter 16

15

 Alcohols from Grignard Reagents

Chapter 12

16

 Alkyl Lithium Reagents

Organolithium reagents react similarly to Grignard

reagents

Chapter 12

17

4. . Predict the products from the addition of water

(hydration) to aldehydes and ketones (PAGE : 746)

Chapter 16

18

Nucleophilic Addition of H2O:

Hydration

Aldehydes and ketones react with water to yield

1,1-diols (geminal (gem) diols) :the

term geminal refers to the relationship between
two atoms or functional groups that are attached to
the same atom.
Hyrdation is reversible: a gem diol can eliminate
water

Base-Catalyzed Addition of Water

Addition of water is catalyzed

by both acid and base

The base-catalyzed hydration
nucleophile is the hydroxide
ion, which is a much stronger
nucleophile than water

Acid-Catalyzed Addition of Water

Protonation of C=O makes

it more electrophilic

5. Predict the products of acetals and hemiacetal from

the addition of Alcohols and describe the formation of
cyclic acetals (PAGE : 748) and its uses as protecting
group. (PAGE : 749)
the addition of an alcohol nucleophile to a ketone or aldehyde.
an alcohol adds to an aldehyde, the result is called a hemiacetal;
when an alcohol adds to a ketone the resulting product is
a hemiketal.

Chapter 16

22

Chapter 16

23

 The Addition of Alcohols: Hemiacetals and

Acetals
Hemiacetals
An aldehyde or ketone dissolved in an alcohol will form an
equilibrium mixture containing the corresponding hemiacetal
A hemiacetal has a hydroxyl and alkoxyl group on the same carbon
Acylic hemiacetals are generally not stable, however, cyclic five- and six-

membered ring hemiacetals are

Chapter 16

24

 Hemiacetal formation is catalyzed by either acid or base

Chapter 16

25

 Dissolving aldehydes (or ketones) in water causes formation of an

equilibrium between the carbonyl compound and its hydrate
The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of

two identical substituents on the same carbon)

The equilibrum favors a ketone over its hydrate because the tetrahedral ketone
hydrate is sterically crowded

Chapter 16

26

 Acetals
An aldehyde (or ketone) in the presence of excess alcohol and an
acid catalyst will form an acetal
H Formation of the acetal proceeds via the corresponding hemiacetal
H An acetal has two alkoxyl groups bonded to the same carbon

Chapter 16

27

 Acetals are stable when isolated and purified

Acetal formation is reversible
H An excess of water in the presence of an acid catalyst will hydrolyze an acetal to

the corresponding aldehyde (or ketone)

Chapter 16

28

 Acetal formation from ketones and simple alcohols is less

favorable than formation from aldehydes
H Formation of cyclic 5- and 6- membered ring acetals from ketones is, however,

favorable
H Such cyclic acetals are often used as protecting groups for aldehydes and
ketones
H These protecting groups can be removed using dilute aqueous acid

Chapter 16

29

 Acetals as Protecting Groups

Acetal protecting groups are stable to most reagents except
aqueous acid
Example: An ester can be reduced in the presence of a ketone
protected as an acetal

Chapter 16

30

6. Predict the products from the addition of amines to

aldehydes and ketones which produce Imines from 1o
Amines (PAGE : 751), Enamines from 2o Amines
(PAGE : 754), Enamines for Alkylation of Ketones
(PAGE : 755)

Chapter 16

31

 The Addition of Primary and Secondary Amines

Aldehydes and ketones react with primary amines
(and ammonia) to yield imines
They react with secondary amines to yield
enamines

Chapter 16

32

 Imines

These reactions occur fastest at pH 4-5

Mild acid facilitates departure of the hydroxyl

group from the aminoalcohol intermediate

without also protonating the nitrogen of the
amine starting compound

Chapter 16

33

Chapter 16

34

 Enamines

Secondary amines cannot form a neutral imine

by loss of a second proton on nitrogen
An enamine is formed instead

Chapter 16

35

Chapter 16

36

7. Predict the products from Wittig Reaction (PAGE :

757-760)

Chapter 16

37

 The Addition of Ylides: The Wittig Reaction

Aldehydes and ketones react with phosphorous
triphenyl phosphonium ylide to produce alkenes
An ylide is a neutral molecule with adjacent
positive and negative charges

Chapter 16

38

Reaction of triphenylphosphine with a primary or

secondary alkyl halide produces a phosphonium salt
The phosphonium salt is deprotonated by a strong base to form

the ylide

Chapter 16

39

 Addition of the ylide to the carbonyl leads to formation of a fourmembered ring oxaphosphetane
The oxaphophetane rearranges to the alkene and triphenylphosphine oxide
The driving force for the last reaction is formation of the very strong

phosphorus-oxygen double bond in triphenylphosphine oxide

Chapter 16

40

 Solved Problem: Make 2-Methyl-1-phenylprop-1-ene by a Wittig

reaction

Chapter 16

41

 Unlike elimination reactions (such as

dehydrohalogenation of alkyl halides), which

produce mixtures of alkene regioisomers
determined by Saytzeff's rule, the Wittig reaction
forms the double bond in one position with no
ambiguity.

Chapter 16

42