Chapter 16

Aldehydes & Ketones:

Nucleophilic Addition
to the Carbonyl Group
Created by
Professor William Tam & Dr. Phillis Chang
Ch. 16 - 1

About The Authors

These PowerPoint Lecture Slides were created and prepared by Professor
William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in
1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an
NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard
University (USA). He joined the Department of Chemistry at the University of
Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and
Associate Chair in the department. Professor Tam has received several awards
in research and teaching, and according to Essential Science Indicators, he is
currently ranked as the Top 1% most cited Chemists worldwide. He has
published four books and over 80 scientific papers in top international journals
such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her
M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She
lives in Guelph with her husband, William, and their son, Matthew.

Ch. 16 - 2

1. Introduction

Carbonyl compounds
O

R
H
aldehyde

R
R'
ketone

O
R

OR'
ester

(R, R' = alkyl, alkenyl, alkynyl or

aryl groups)

Ch. 16 - 3

2. Nomenclature of Aldehydes &

Ketones

Rules
Aldehyde as parent (suffix)
Ending with al;
Ketone as parent (suffix)
Ending with one
Number the longest carbon chain
containing the carbonyl carbon and
starting at the carbonyl carbon
Ch. 16 - 4

Examples
Cl
5

O
4-Chloro-2,2-dimethylpentanal

Br
1

O
6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 5

group as a prefix: methanoyl

or formyl group
O

group as a prefix: ethanoyl or

acetyl group (Ac)

O

groups as a prefix: alkanoyl or

acyl groups

Ch. 16 - 6

CO2H O
H

2-Methanoylbenzoic acid
(o-formylbenzoic acid)

SO3H

O
4-Ethanoylbenzenesulfonic acid
(p-acetylbenzenesulfonic acid)
Ch. 16 - 7

3. Physical Properties
O

OH

H
Butane

Propanal

Butane

1-Propanol

bp -0.5oC

bp 49oC

bp 56.1oC

bp 97.2oC

(MW = 58)

(MW = 58)

(MW = 58)

(MW = 60)

Ch. 16 - 8

4. Synthesis of Aldehydes
4A. Aldehydes by Oxidation of 1o
Alcohols
O

PCC
R

OH

Ch. 16 - 9

e.g.
PCC

OH

CH2Cl2

OH

O
(90%)

PCC
CH2Cl2

(89%)

Ch. 16 - 10

4B. Aldehydes by Ozonolysis of

Alkenes
R

R"

R'

1. O3
2. Me2S

R"
O

R'

Ch. 16 - 11

e.g.
1. O3, CH2Cl2, -78oC

2. Me2S
+

O
H

H
1. O3, CH2Cl2, -78oC
H3C

2. Me2S

O
H3C

O
+

Ch. 16 - 12

4C. Aldehydes by Reduction of Acyl

Chlorides, Esters, and Nitriles
O
R

OH
or
O

O
OR'

or

LiAlH4

LiAlH4

OH

O
R

Cl
or

Ch. 16 - 13

LiAlH4 is a very powerful reducing

agent, and aldehydes are easily
reduced
Usually reduced all the way to the
o
corresponding 1 alcohol
Difficult to stop at the aldehyde
stage
Not a good method to
synthesize aldehydes using
LiAlH4
Ch. 16 - 14

Two derivatives of aluminum hydride

that are less reactive than LAH

O Bu
Li

Al

OtBu

OtBu
Lithium tri-tert-butoxy
aluminum hydride

Al

Diisobutylaluminum hydride
(abbreviated i-Bu2AlH or DIBAL-H)

Ch. 16 - 15

O
R

1. LiAlH(OtBu)3, -78oC
Cl

2. H2O

Acyl chloride
O
R

1. DIBAL-H, hexane, -78oC

OR'

2. H2O

Ester
1. DIBAL-H, hexane
R

Nitrile

2. H2O
Ch. 16 - 16

Aldehydes from acyl chlorides: RCOCl

RCHO
O

SOCl2

Et2O, -78oC

Cl 2. H2O

OH

1. LiAlH(OtBu)3,

e.g.
O

O
1. LiAlH(OtBu)3, Et2O, -78oC

Cl

2. H2O
CH3

CH3
Ch. 16 - 17

Reduction of an Acyl Chloride to an Aldehyde

O

LiAlH(OtBu)3

O
R

Cl

Li

+ Al(OtBu)3

Cl

Li
R

Al(OtBu)3

O
R

Li

Al(OtBu)3

Cl

Cl

-LiCl

O
R

C
H

Al(OtBu)3

H2O

O
R

C
H

Ch. 16 - 18

Aldehydes from esters and nitriles:

RCO2R RCHO
RCN RCHO
Both esters and nitriles can be
reduced to aldehydes by DIBAL-H

Ch. 16 - 19

Reduction of an ester to an aldehyde

O
R

Al(i-Bu)2

C
OR'

Al(i-Bu)2

O
R

O
R

H
OR'

C
H

H2O

Al(i-Bu)2

OR'
Ch. 16 - 20

10

Reduction of a nitrile to an aldehyde

Al(i-Bu)2

O
R

Al(i-Bu)2

H2O

N
R

Al(i-Bu)2

C
H

Ch. 16 - 21

Examples
O

(1)

O
O

1. DIBAL-H, hexane, -78oC

H
OH

2. H2O

(2)

1. DIBAL-H, hexane, -78oC

2. H2O

O
H
Ch. 16 - 22

11

5. Synthesis of Ketones
5A. Ketones from Alkenes, Arenes,
and 2o Alcohols

R
R'

Ketones (and aldehydes) by ozonolysis

of alkenes
R"
H

1. O3
2. Me2S

R"
O

R'

H
Ch. 16 - 23

(i)

Examples

O
1. O3
2. Me2S
O

(ii)

1. O3
2. Me2S
O
H

+ O
Ch. 16 - 24

12

Ketones from arenes by FriedelCrafts

acylations
O
O
+

AlCl3
Cl

+ HCl

an alkyl aryl
ketone

Ch. 16 - 25

Ketones from secondary alcohols by

oxidation
OH
R

H2CrO4
R'

or PCC

R'

Ch. 16 - 26

13

5B. Ketones from Nitriles

1. R'M, Et2O

2. H3O+

N
R

R'

M
R'

Ch. 16 - 27

Examples
1. MeLi, Et2O
C

2. H3O

Me

O
C

1.

MgBr , Et2O

2. H3O+

Ch. 16 - 28

14

Suggest synthesis of
O

Br

from

and

HO

Ch. 16 - 29

Retrosynthetic analysis
O
HO

5 carbons here

4 carbons here
need to add
one carbon

Ch. 16 - 30

15

Retrosynthetic analysis
O

disconnection

MgBr
+ N

disconnection
NC

+
Br

HO
Ch. 16 - 31

Synthesis
PBr3

HO

Br

NaCN
DMSO

MgBr
1.
O
Et2O
2. H3O

Ch. 16 - 32

16

Suggest synthesis of
O

Br

from

and

HO

Ch. 16 - 33

Retrosynthetic analysis
O
HO

5 carbons here

5 carbons here
no need to
add carbon

Ch. 16 - 34

17

Retrosynthetic analysis
O

MgBr
+

disconnection
HO

Ch. 16 - 35

Synthesis
PCC

HO

O
MgBr
1.

, Et 2O

2. H3O+
OH

O
PCC

Ch. 16 - 36

18

6. Nucleophilic Addition to the

CarbonOxygen Double Bond

Structure

~ 120o
C

~ 120o

Nu

~ 120o

Carbonyl carbon: sp2 hybridized

Trigonal planar structure

Ch. 16 - 37

Polarization and resonance structure

O

O
C

Nucleophiles will attack the

nucleophilic carbonyl carbon
Note: nucleophiles usually do not
attack non-polarized C=C bond
Ch. 16 - 38

19

With a strong nucleophile:

R'

Nu

C O

Nu:

R'

O:

R
H

Nu

Nu
Nu:

R'
R

Ch. 16 - 39

Also would expect nucleophilic addition

reactions of carbonyl compounds to be
catalyzed by acid (or Lewis acid)
O
C

+ H+

O
C

(protonated carbonyl group)

Note: full positive charge on the

carbonyl carbon in one of the
resonance forms
Nucleophiles readily attack

Ch. 16 - 40

20

Mechanism

R'

+ H
C O

(or a Lewis acid)

R'

R'
C

OH

+ A:

OH

Ch. 16 - 41

Mechanism

R'

:Nu

OH

+ H

Nu

:Nu

R'
R

+ A:

R'

R
Ch. 16 - 42

21

6A. Reversibility of Nucleophilic

Additions to the CarbonOxygen
Double Bond

Many nucleophilic additions to carbon

oxygen double bonds are reversible;
the overall results of these reactions
depend, therefore, on the position of
an equilibrium

Ch. 16 - 43

6B. Relative Reactivity: Aldehydes

vs. Ketones
O

>
R

>
R

R'

OR'

Ch. 16 - 44

22

Steric factors
O
R

Nu
H

Nu

smal
l
O
R

Nu
R'

Nu

R'

large
Ch. 16 - 45

Electronic factors
(positive inductive effect from
both R & R' groups) carbonyl
carbon less + (less
nucleophilic)

C<
R > H

C<
R > R'

(positive inductive
effect from only
one R group)
Ch. 16 - 46

23

7. The Addition of Alcohols:

Hemiacetals and Acetals

Acetal & Ketal Formation: Addition of

Alcohols to Aldehydes
O

H+

+ R"OH
R

R'

Catalyzed
by acid
acetal (R' = H)
ketal (R' = alkyl)

H+

OH hemi-acetal
(R' = H)
R' hemi-ketal
(R' = alkyl)

R"OH
R"O

OR"

R'

Ch. 16 - 47

Mechanism
O

R"O

R'

+ R"OH

OH
R

O
R'

O:

H+

H
R"

R'

R"
H

H
R'

+ R"OH
Ch. 16 - 48

24

Mechanism (Contd)

hemi-acetal (R' = H) or
hemi-ketal (R' = alkyl)

OH
R

R"OH

OH
R

R"

R'

H2O +
R

OR"

R"

R'

R"

O
H

OH2
R

R'

OR"
R'
Ch. 16 - 49

Mechanism (Contd)
O
R

R"
R"OH
R'

OR"
R

H
R"

R'

R"OH

acetal (R' = H) or
ketal (R' = alkyl)

OR"
R

OR"
R'
Ch. 16 - 50

25

Note: All steps are reversible. In the

presence of a large excess of
anhydrous alcohol and catalytic
amount of acid, the equilibrium
strongly favors the formation of acetal
(from aldehyde) or ketal (from ketone)
On the other hand, in the presence of
a large excess of H2O and a catalytic
amount of acid, acetal or ketal will
hydrolyze back to aldehyde or ketone.
This process is called hydrolysis

Ch. 16 - 51

Acetals and ketals are stable in neutral

or basic solution, but are readily
hydrolyzed in aqueous acid
OR"

OR" + H2O
R'

H+
R

R'

+ 2 R"OH

Ch. 16 - 52

26

Aldehyde hydrates: gem-diols

H3C
O + H2O

H3C

Hydrate
(a gem-diol)

Acetaldehyde

Ch. 16 - 53

Mechanism

H3C

OH2

C O

HO
R

H3C
H

OH
H

OH2
O:

H3C

OH

OH

distillation
R

+ H2O

Ch. 16 - 54

27

7A. Hemiacetals
H

O
O

Butanal-4-ol

Hemiacetal: OH & OR groups

bonded to the same carbon

OH
A cyclic
hemiacetal
Ch. 16 - 55

OH

Hemiacetal: OH & OR
groups bonded to the
same carbon

HO
HO

OH
OH

(+)-Glucose
(A cyclic hemiacetal)

Ch. 16 - 56

28

7B. Acetals
OH

A ketal
O

HO
HO

OH

HO

O
HO

OH

An acetal

OH

Sucrose
(table sugar)
Ch. 16 - 57

Cyclic acetal formation is favored when

a ketone or an aldehyde is treated with
an excess of a 1,2-diol and a trace of
acid
O

H3O+

+ HO

OH

R'

Ketone

(excess)

R'

Cyclic acetal
+ H2O
Ch. 16 - 58

29

This reaction, too, can be reversed by

treating the acetal with aqueous acid

R'

H3O+

+ H2O

O
R

R'
+

HO

OH

Ch. 16 - 59

7C. Acetals Are Used as Protecting Groups

Although acetals are hydrolyzed to
aldehydes and ketones in aqueous acid,

acetals are stable in basic solutions

R'O
R

O
R

OR"

OH

H2O

O
R'

OH
H2O

No Reaction

No Reaction

Acetals are used to protect aldehydes and

ketones from undesired reactions in basic
solutions
Ch. 16 - 60

30

Example
Attempt to
synthesize:

OH

O
Br

from:

Ch. 16 - 61

Synthetic plan
O
+

BrMg
O

OH

This route will not work

Ch. 16 - 62

31

Reason:
(a) Intramolecular nucleophilic addition
O

BrMg

(b) Homodimerization or polymerization

O
BrMg

O
BrMg

O
BrMg

Ch. 16 - 63

Thus, need to protect carbonyl group first

HO

Br
O

O
OH

HO

aqueous H+

, H+
OMgBr

Br
O
Mg
Et2O

(ketal)
O

BrMg

O
Ch. 16 - 64

32

7D. Thioacetals

Aldehydes & ketones react with thiols

to form thioacetals
O

EtS

2 EtSH
HA

SEt

+ H2O

Thioacetal
O
R

SH

HS
R'

BF3

R
R'
Cyclic
thioacetal

+ H2O

Ch. 16 - 65

Thioacetal formation with subsequent

desulfurization with hydrogen and
Raney nickel gives us an additional
method for converting carbonyl groups
of aldehydes and ketones to CH2
groups

R'

H2, Raney Ni

H
R

H
R'

+ HS

SH

+ NiS
Ch. 16 - 66

33

8. The Addition of Primary and

Secondary Amines

Aldehydes & ketones react with 1o

amines to form imines and with 2o
amines to form enamines

From a 1o amine
R

From a 2o amine
R3

R1

R2
R1
Imine

R5

R2
R4
Enamine

R1,
R4,

R2, R3 = C or H;
R5 = C
Ch. 16 - 67

8A. Imines

Addition of 1o amines to aldehydes &

ketones

R
O
R'

H2N
o

R"

(1 amines)

H+

R
N
R'

R"

+ H2O

(imines)
[(E) & (Z) isomers]

Ch. 16 - 68

34

Mechanism

O
R

H3O
R'

O
R

H
R'

H2NR"

H
H
N

R
R'

R"

-H+
R

OH2

H
N

R'

NHR"

H+

H
NHR"

R'

R'

R"

(amino alcohol)

H2O
R
N
R'

R"

Ch. 16 - 69

Similar to the formation of acetals and

ketals, all the steps in the formation of
imine are reversible. Using a large
excess of the amine will drive the
equilibrium to the imine side
Hydrolysis of imines is also possible by
adding excess water in the presence of
catalytic amount of acid

R
+ H2O

N
R'

R"

H+

R
O + H2NR"
R'
Ch. 16 - 70

35

8B. Oximes and Hydrazones

Imine formation reaction with a 1o amine

R
C

+ H2N

a 1o amine

aldehyde
or ketone

+ H2O

an imine
[(E) & (Z) isomers]

Oxime formation reaction with

hydroxylamine
OH
C

O + H2N

aldehyde
or ketone

OH

hydroxyl
amine

+ H2O

an oxime
[(E) & (Z) isomers]
Ch. 16 - 71

Hydrazone formation reaction with

hydrazine
C

NH2

O + H2NNH2

a hydrazone

aldehyde hydrazine
or ketone

+ H2O

Enamine formation reaction with a 2o

amine
R

O
C
H

+ H

R
2o amine

cat. HA

N
C

enamine

R
+ H2O

Ch. 16 - 72

36

8C. Enamines
R1
H

R4

O
R3

+ H

N
R

R2

R5

cat. HA

R5

R1

R3

R2

2o amine

enamine
+ H2O

Ch. 16 - 73

Mechanism
O
C
H

N
R

O
C
H

H
N

aminoalcohol
intermediate
Ch. 16 - 74

37

Mechanism (Contd)
O

H
N

R
N
:A

+ H2O +

H
iminium ion
intermediate
Ch. 16 - 75

Mechanism (Contd)

R
N
C

H
A:

Ch. 16 - 76

38

9. The Addition of Hydrogen

Cyanide: Cyanohydrins

Addition of HCN to aldehydes & ketones

O
R

OH

HCN
R

R'

CN
R' (cyanohydrin)

CN
R

H+
CN

R'
Ch. 16 - 77

Mechanism
O
R

CN
R'

(slow)

CN
R'

NC

OH
R

CN
R'
Ch. 16 - 78

39

Slow reaction using HCN since HCN is a

weak acid and a poor source of
nucleophile
Can accelerate reaction by using NaCN
or KCN and slow addition of H2SO4

O
R

O Na
R'

NaCN

OH
H2SO4

R'

CN

CN
R'

Ch. 16 - 79

Synthetic applications
HO

HCl, H2O

heat

O
R

HCN
R'

HO
R

R'
(-hydroxy acid)

CN

95% H2SO4

R'

heat

1. LiAlH4
2. H2O

COOH

COOH
R

R'
(,-unsaturated acid)
HO
R

NH2

R'
(-aminoalcohol)
Ch. 16 - 80

40

10. The Addition of Ylides: The

Wittig Reaction
R"

R
O

(C6H5)3P

R"
phosphorus ylide
(or phosphorane)

R'
aldehyde
or ketone

R"
C

R'

R"

alkene
[(E) & (Z) isomers]
+
O P(C6H5)3
triphenylphosphine
oxide

Ch. 16 - 81

Phosphorus ylides
R"
(C6H5)3P

R"

(C6H5)3P

R"

R"

R"
(C6H5)3P: +

R"
CH

R"'

(C6H5)3P

CH

R"'
an alkyltriphenylphosphonium halide

triphenylphosphine

R"
(C6H5)3P

C
R"'

R"
H

:B

(C6H5)3P

R"'
a phosphorus
ylide

+ H:B

Ch. 16 - 82

41

Example
C6H6

(C6H5)3P: + CH3Br

(C6H5)3P

CH3

Br

Methyltriphenylphosphonium bromide
(89%)

(C6H5)3P

CH3

C6H5Li

(C6H5)3P

Br

CH2:

+ C6H6 + LiBr

Ch. 16 - 83

Mechanism of the Wittig reaction

R'

R"
+

:C

:O:

R' R"
R"'

P(C6H5)3

:O

ylide

aldehyde
or ketone

: :

P(C6H5)3

R"'

P(C6H5)3

R"
C

R
triphenylphosphine
oxide

oxaphosphetane

R'
O

C
R"

alkene
(+ diastereomer)

Ch. 16 - 84

42

10A. How to Plan a Witting Synthesis

Synthesis of
using a Wittig reaction

Ch. 16 - 85

Retrosynthetic analysis
route 1

disconnection
route 2

O
+ Ph3P

Ph3P: + Br

PPh3
+ O

Br
+ :PPh3
Ch. 16 - 86

43

Synthesis Route 1
:PPh3

Br

Br

Ph3P
n

BuLi

Ph3P

Ch. 16 - 87

Synthesis Route 2
Br

PPh3 Br

:PPh3

BuLi

PPh3

Ch. 16 - 88

44

10B. The HornerWadsworthEmmons

Reaction
NaH

O
P

O
P

OEt
OEt

a phosphonate
ester

OEt
OEt

+ H2

Ch. 16 - 89

O
O
P

OEt
OEt

O
+

EtO P
EtO

Na

84%
Ch. 16 - 90

45

The phosphonate ester is prepared by

reaction of a trialkyl phosphite [(RO)3P]
with an appropriate halide (a process
called the Arbuzov reaction)
OEt
X

+
EtO

OEt

Triethyl phosphite
O

EtX +

OEt
OEt

Ch. 16 - 91

11. Oxidation of Aldehydes

O
R

KMnO4, OH
H

or Ag2O, OH

H 3O +
O
R

OH
Ch. 16 - 92

46

12. Chemical Analyses for Aldehydes

and Ketones
12A. Derivatives of Aldehydes & Ketones
H

R
O + H2N

NO2

R'
O2N

hydrazine
R
N

R'

hydrazone
(orange ppt.)

NO2

H
O2N

Ch. 16 - 93

12B. Tollens Test (Silver Mirror Test)

O
R

Ag(NH3)2
H

H2O

+ Ag
silver
mirror

Ch. 16 - 94

47

13. Spectroscopic Properties of

Aldehydes and Ketones
13A. IR Spectra of Aldehydes and Ketones
C=O Stretching Frequencies
Compound

Range (cm)

Compound

Range (cm)

1720 - 1740

RCOR

1705 - 1720

1695 - 1715

ArCOR

1680 - 1700

1680 - 1690

1665 - 1680

CHO

Ar

CHO

C
CHO

C
COR

Cyclohexanone

1715

Cyclopentanone 1751
Cyclobutanone

1785

Ch. 16 - 95

Conjugation of the carbonyl group with

a double bond or a benzene ring shifts
the C=O absorption to lower
frequencies by about 40 cm-1
O

single bond

Ch. 16 - 96

48

Ch. 16 - 97

13B. NMR Spectra of Aldehydes and

Ketones
13C

NMR spectra
The carbonyl carbon of an aldehyde
or ketone gives characteristic NMR
signals in the 180220 ppm
region of 13C spectra

Ch. 16 - 98

49

 1H

NMR spectra

An aldehyde proton gives a distinct 1H

NMR signal downfield in the 912 ppm
region where almost no other protons
absorb; therefore, it is easily identified
Protons on the carbon are deshielded
by the carbonyl group, and their signals
generally appear in the 2.02.3 ppm
region
Methyl ketones show a characteristic
(3H) singlet near 2.1 ppm
Ch. 16 - 99

Ch. 16 - 100

50

Ch. 16 - 101

14. Summary of Aldehyde and

Ketone Addition Reactions
NR2

RO

OR

OH
1. RM

R2NH

R-NH2, H+

2. H3O

2 ROH, H+
R

PPh3

OH

1. LiAlH4 or NaBH4
2. H3O+

1. NaCN
2. H3O

OH
CN
Ch. 16 - 102

51

 END OF CHAPTER 16

Ch. 16 - 103

52