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
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
3
4
H
1
2
O
4-Chloro-2,2-dimethylpentanal
Br
1
2
3
4
5
6
7
O
6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 5
O

H
group as a prefix: methanoyl
or formyl group
O
group as a prefix: ethanoyl or

acetyl group (Ac)
O

R
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
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 1
Alcohols
O
PCC
R
OH
o
R
H
Ch. 16 - 9

e.g.
PCC
OH
CH2Cl2
OH
O
(90%)
H
O
PCC
CH2Cl2
(89%)
H
Ch. 16 - 10
4B. Aldehydes by Ozonolysis of
Alkenes
R
R'
R"
H
1. O3
2. Me2S
R
R"
O
R'
+
O
H
Ch. 16 - 11

e.g.
1. O3, CH2Cl2, -78oC
O
2. Me2S
+
O
H
H
1. O3, CH2Cl2, -78oC
H3C
2. Me2S
O
H3C
O
+
H
H
Ch. 16 - 12
4C. Aldehydes by Reduction of Acyl
Chlorides, Esters, and Nitriles
O
R
OH
or
O
R
O
OR'
or
LiAlH 4
R
H
LiAlH 4
R
OH
O
R
Cl
or
R
C
N
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
OtBu
Li+
H
Al

OtBu
OtBu
Lithium tri- tert-butoxy
aluminum hydride
R
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
O
o
1. DIBAL-H, hexane, -78 C
OR'
2. H2O
R
H
Ester
1. DIBAL-H, hexane
R
C
Nitrile
N
2. H2O
Ch. 16 - 16

Aldehydes from acyl chlorides: RCOCl
 RCHO
O
R

O
SOCl 2
OH
R
1. LiAlH(OtBu)3,
O
o
Et2O, -78 C
Cl 2. H2O
R
H
e.g.
O
O
Cl
1. LiAlH(OtBu)3, Et2O, -78oC
H
2. H2O
CH3
CH3
Ch. 16 - 17

Reduction of an Acyl Chloride to an Aldehyde
O
R
LiAlH(OtBu)3
C
O
R
C
Cl
Li
+ Al(OtBu)3
Cl
H
Li
R
O
Al(O tBu)3
C
H
O
R
Li
C
H
Al(O tBu)3
Cl
Cl
-LiCl
O
R
C
H
Al(O tBu)3
H2O
O
R
C
H
Ch. 16 - 18

Aldehydes from esters and nitriles:
RCO2R’  RCHO
RC≡N  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
C
OR'
H
O
R
H
C
H
H2O
R
O
Al(i-Bu)2
C
H
OR'
Ch. 16 - 20

Reduction of a nitrile to an aldehyde
R
C
Al( i-Bu)2
N
R
C
N
H
H
O
R
Al(i-Bu)2
C
H
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)
C
N
1. DIBAL-H, hexane, -78oC
2. H2O
O
H
Ch. 16 - 22
5. Synthesis of Ketones
5A. Ketones from Alkenes, Arenes,
o
and 2 Alcohols

R
R'
Ketones (and aldehydes) by ozonolysis
of alkenes
R"
H
1. O3
2. Me2S
R
R"
O
R'
+
O
H
Ch. 16 - 23

(i)
Examples
O
1. O3
2. Me2S
O
(ii)
1. O3
2. Me2S
O
H
+ O
Ch. 16 - 24

Ketones from arenes by Friedel–Crafts
acylations
O
O
+
R
AlCl 3
R
Cl
+ HCl
an alkyl aryl
ketone
Ch. 16 - 25

Ketones from secondary alcohols by
oxidation
OH
R
O
H2CrO4
R'
or PCC
R
R'
Ch. 16 - 26
5B. Ketones from Nitriles
R
C
N
O
1. R'M, Et2O
R
2. H3O+
N
R
R'
M
R'
Ch. 16 - 27

Examples
1. MeLi, Et2O
C
N
2. H3O+
Me
O
O
C
N
1.
MgBr , Et2O
2. H3O+
Ch. 16 - 28

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

Retrosynthetic analysis
O
disconnection
MgBr
+ N
C
disconnection
NC
+
Br
HO
Ch. 16 - 31

Synthesis
PBr3
HO
Br
NaCN
DMSO
MgBr
1.
O
Et2O
2. H3O+
N
C
Ch. 16 - 32

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

Retrosynthetic analysis
O
O
MgBr
+
H
disconnection
HO
Ch. 16 - 35

Synthesis
PCC
HO
O
MgBr
1.
, Et2O
2. H3O+
OH
O
PCC
Ch. 16 - 36
6. Nucleophilic Addition to the
Carbon–Oxygen Double Bond

Structure


O
~ 120o
C
~ 120o
⊖
Nu
~ 120o
● Carbonyl carbon: sp2 hybridized
● Trigonal planar structure
Ch. 16 - 37

Polarization and resonance structure
O

C

O
C
● Nucleophiles will attack the
nucleophilic carbonyl carbon
● Note: nucleophiles usually do not
attack non-polarized C=C bond
Ch. 16 - 38

With a strong nucleophile:
R'
Nu:

Nu



C O
C
R'
R
O:
R
H
Nu
O
H
Nu
Nu:
+
C
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
H
O
H
C
(protonated carbonyl group)
● Note: full positive charge on the
carbonyl carbon in one of the
resonance forms
 Nucleophiles readily attack
Ch. 16 - 40

Mechanism
R'
 
+ H
C O
R
(or a Lewis acid)
R'
R'
C
R
A
C
OH
OH
+ A:
R
Ch. 16 - 41
Mechanism

R'
C
:Nu
OH
H
R
H
+ H
Nu
:Nu
C
R'
R
A
O
H
+ A:
C
R'
O
H
R
Ch. 16 - 42
6A. Reversibility of Nucleophilic
Additions to the Carbon–Oxygen
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
O
O
>
R
H
>
R
R'
R
OR'
Ch. 16 - 44

Steric factors
O
R
O
Nu
H
R
smal
l
O
R
H
O
Nu
R'
Nu
R
Nu
R'
large
Ch. 16 - 45

Electronic factors
(positive inductive effect from
both R & R' groups)  carbonyl
carbon less + (less
nucleophilic)



O

O
C<
>
R  H
C<
>
R  R'
(positive inductive
effect from only
one R group)
Ch. 16 - 46
7. The Addition of Alcohols:
Hemiacetals and Acetals

Acetal & Ketal Formation: Addition of
Alcohols to Aldehydes
O
+ R"OH
R
H+
R"O
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
R'
Ch. 16 - 47

Mechanism
O
R
C
O:
+
R'
+ R"OH
OH
R
O
R'
H
R
O
H
R"
C
R
C
R'
+
H
O
R"
H
H
R'
+ R"OH
Ch. 16 - 48

Mechanism (Cont’d)
hemi-acetal (R' = H) or
hemi-ketal (R' = alkyl)
OH
R
O
H
R"OH
OH
R
R"
R'
O
H2O +
R
C
OR"
R'
R"
R"
H
H
OH2
R
R'
+
O
OR"
R'
Ch. 16 - 49

Mechanism (Cont’d)
O
R
C
R"
R"OH
R'
OR"
R
O
H
R"
R'
R"OH
acetal (R' = H) or
ketal (R' = alkyl)
OR"
R
OR"
R'
Ch. 16 - 50
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"
R
OR" + H2O
R'
O
H+
R
R'
+ 2 R"OH
Ch. 16 - 52

Aldehyde hydrates: gem-diols
H3C
O + H2O
H
Acetaldehyde
H3C
O
H
H
O
H
Hydrate
(a gem-diol)
Ch. 16 - 53

Mechanism
H3C
OH2
H
C O 


HO
R
H3C
H
OH
H
OH2
O:
H3C
OH
H
OH
O
distillation
R
H
+ H2O
Ch. 16 - 54
7A. Hemiacetals
H
O
O
H
O
Butanal-4-ol
O
O
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
O
HO
HO
OH
OH
(+)-Glucose
(A cyclic hemiacetal)
Ch. 16 - 56
7B. Acetals
OH
A ketal
O
HO
HO
OH
HO
O
HO
O
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
R
H3O+
+ HO
OH
R'
Ketone
(excess)
O
O
R
R'
Cyclic acetal
+ H2O
Ch. 16 - 58

This reaction, too, can be reversed by
treating the acetal with aqueous acid
O
R
O
+ H2O
H3O+
O
R
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"
H
O
R'
OH
H2O
OH
H2O
No Reaction
No Reaction
Acetals are used to protect aldehydes and
ketones from undesired reactions in basic
solutions
Ch. 16 - 60

Example
Attempt to
synthesize:
OH
O
from:
Br
O
Ch. 16 - 61
● Synthetic plan
O
+
BrMg
O
OH
O

This route will not work
Ch. 16 - 62
Reason:
(a) Intramolecular nucleophilic addition


BrMg
O

(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
O
(ketal)
O
O

BrMg

O
O
O
Ch. 16 - 64
7D. Thioacetals

Aldehydes & ketones react with thiols
to form thioacetals
O
R
EtS
2 EtSH
HA
H
SEt
R
+ H2O
H
Thioacetal
O
R
SH
HS
R'
BF3
S
S
R
R'
Cyclic
thioacetal
+ H2O
Ch. 16 - 65

S
R
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
S
R'
H2, Raney Ni
H
R
H
R'
+ HS
SH
+ NiS
Ch. 16 - 66
8. The Addition of Primary and
Secondary Amines

o
Aldehydes & ketones react with 1
o
amines to form imines and with 2
amines to form enamines
o
o
From a 1 amine
N
R3
R2
R1
Imine
From a 2 amine
R3
R1
N
R2
R4
Enamine
R5
R1,
R4,
R2, R3 = C or H;
R5 = C
Ch. 16 - 67
8A. Imines

o
Addition of 1 amines to aldehydes &
ketones
R
O
R'
+
H2N
R"
(1o amines)
+
H
R
N
R'
R"
+ H2O
(imines)
[(E) & (Z) isomers]
Ch. 16 - 68
Mechanism

+
O
R
O
H3O
R'
R
H
O
H
H
R'
H2NR"
R
N
R'
R"
H
-H+
R
OH2
H
N
R'
R
R"
H2O
NHR"
R'
H+
O
R
H
NHR"
R'
(amino alcohol)
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
8B. Oximes and Hydrazones

o
Imine formation – reaction with a 1 amine
R
C
O
aldehyde
or ketone

+ H2N
R
a 1o amine
C
N
+ H2O
an imine
[(E) & (Z) isomers]
Oxime formation – reaction with
hydroxylamine
OH
C
O + H2N
aldehyde
or ketone
OH
hydroxyl
amine
C
N
+ H2O
an oxime
[(E) & (Z) isomers]
Ch. 16 - 71

Hydrazone formation – reaction with
hydrazine
C
NH2
O + H2NNH2
C
+ H2O
a hydrazone
aldehyde hydrazine
or ketone

N
Enamine formation – reaction with a 2
amine
R
O
C
H
C
+ H
N
R
R
2o amine
cat. HA
N
C
C
enamine
o
R
+ H2O
Ch. 16 - 72
8C. Enamines
R
O
R1
H
4
C
2
R
3
R
+ H
N
R5
R4
2o amine
cat. HA
N
R1
R5
R3
R2
enamine
+ H2O
Ch. 16 - 73

Mechanism
O
C
H
C
+
H
N
R
R
C
O
R
C
N
H
H
O
C
H
R
C
H
N
R
R
aminoalcohol
intermediate
Ch. 16 - 74

Mechanism (Cont’d)
O
A
H
+
C
H
C
H
H
N
C
R
H
O
C
N
H
R
R
R
R
N
:A
+ H2O +
C
C
R
H
iminium ion
intermediate
Ch. 16 - 75

Mechanism (Cont’d)
R
N
C
H
A:
C
R
R
C
C
N
R + H
A
H
enamine
Ch. 16 - 76
9. The Addition of Hydrogen
Cyanide: Cyanohydrins

Addition of HCN to aldehydes & ketones
O
R
OH
HCN
R
R'
CN
R' (cyanohydrin)
O
CN
R
H+
CN
R'
Ch. 16 - 77

Mechanism
O
R
O
CN
R'
(slow)
R
CN
R'
NC
H
OH
R
CN
R'
Ch. 16 - 78
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
R
R'
CN
OH
H2SO4
R
CN
R'
Ch. 16 - 79

Synthetic applications
HO
HCl, H2O
R
heat
O
R
HCN
R'
HO
R
CN
R'
R'
(-hydroxy acid)
COOH
95% H2SO4
heat
1. LiAlH4
2. H2O
COOH
R
R'
(,-unsaturated acid)
HO
R
NH2
R'
(-aminoalcohol)
Ch. 16 - 80
10. The Addition of Ylides: The
Wittig Reaction
R"
R
O
R'
aldehyde
or ketone
+
(C6H5)3P
R
C
R"
phosphorus ylide
(or phosphorane)
R"
C
R'
C
R"
alkene
[(E) & (Z) isomers]
+
O P(C6H5)3
triphenylphosphine
oxide
Ch. 16 - 81

Phosphorus ylides
R"
(C6H5)3P
R"
C
(C6H5)3P
C
R"
R"
R"
(C6H5)3P: +
R"
CH
R"'
X
(C6H5)3P
CH
R"'
an alkyltriphenylphosphonium halide
triphenylphosphine
R"
(C6H5)3P
C
R"'
X
R"
H
:B
(C6H5)3P
C
R"'
a phosphorus
ylide
+ H:B
Ch. 16 - 82

Example
(C6H5)3P: + CH3Br
C6H6
(C6H5)3P
CH3
Br
Methyltriphenylphosphonium bromide
(89%)
(C6H5)3P
Br
CH3
+
C6H5Li
(C6H5)3P
CH2:
+ C6H6 + LiBr
Ch. 16 - 83

R
Mechanism of the Wittig reaction
R'
C
:O:
R"
+
:C
R' R"
R"'
R
P(C6H5)3
:
:O
ylide
aldehyde
or ketone
: :
P(C6H5)3
+
R"'
P(C6H5)3
R"
C
R
triphenylphosphine
oxide
C
oxaphosphetane
R'
O
C
C
R"
alkene
(+ diastereomer)
Ch. 16 - 84
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

Br
Synthesis – Route 1
:PPh 3
Br
Ph3P
n
BuLi
O
Ph3P
Ch. 16 - 87

Synthesis – Route 2
Br
PPh3 Br
:PPh 3
n
BuLi
O
PPh3
Ch. 16 - 88
10B. The Horner–Wadsworth–Emmons
Reaction
NaH
O
P
O
P
OEt
OEt
a phosphonate
ester
OEt
OEt
+ H2
Ch. 16 - 89
O
O
P
+
H
OEt
OEt
O
+
EtO P
EtO
O
Na
84%
Ch. 16 - 90

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
P
OEt
Triethyl phosphite
EtX +
O
P
OEt
OEt
Ch. 16 - 91
11. Oxidation of Aldehydes
O
R
O
KMnO4, OH
H
or Ag2O, OH
O
R
+
H3O
O
R
OH
Ch. 16 - 92
12. Chemical Analyses for Aldehydes
and Ketones
12A. Derivatives of Aldehydes & Ketones
H
R
O + H2N
N
NO2
R'
O2N
H
hydrazine
R
N

R'
hydrazone
(orange ppt.)
N
NO2
H
O2N
Ch. 16 - 93
12B. Tollens’ Test (Silver Mirror Test)
O
R
O
Ag(NH 3)2
H
H2O
R
O
+ Ag
silver
mirror
Ch. 16 - 94
13. Spectroscopic Properties of
Aldehydes and Ketones
13A. IR Spectra of Aldehydes and Ketones
C=O Stretching Frequencies
Compound
Range (cm)
Compound
Range (cm)
R
1720 - 1740
RCOR
1705 - 1720
1695 - 1715
ArCOR
1680 - 1700
1680 - 1690
C
1665 - 1680
CHO
Ar
C
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
O
single bond
Ch. 16 - 96
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  180–220 ppm
region of 13C spectra
Ch. 16 - 98
 1H
NMR spectra
● An aldehyde proton gives a distinct 1H
NMR signal downfield in the  9–12 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  2.0–2.3 ppm
region
● Methyl ketones show a characteristic
(3H) singlet near  2.1 ppm
Ch. 16 - 99
Ch. 16 - 100
Ch. 16 - 101
14. Summary of Aldehyde and
Ketone Addition Reactions
NR2
N
RO
OR
R
OH
1. RM
R2NH
R-NH2, H+
H
2. H3O+
+
O
1. LiAlH4 or NaBH4
H
2. H3O
2 ROH, H
R
OH
+
+
R
R
PPh3
1. NaCN
2. H3O+
OH
CN
Ch. 16 - 102
 END OF CHAPTER 16 
Ch. 16 - 103