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 [Link]. 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 [Link]. at New York University (USA) in 1994, her
[Link]. 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 O

R H R R' R OR'
aldehyde ketone 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 4 3 2 1 H

O
4-Chloro-2,2-dimethylpentanal

Br

2 3 4 5 6
1 7

O
6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 5
 O
 group as a prefix: methanoyl
H
or formyl group

O
 group as a prefix: ethanoyl or
acetyl group (Ac)

O
 groups as a prefix: alkanoyl or
R
acyl groups
Ch. 16 - 6
 CO2H O

2-Methanoylbenzoic acid SO3H

(o-formylbenzoic acid)

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
o
4A. Aldehydes by Oxidation of 1
Alcohols

PCC O
R OH
R H

Ch. 16 - 9
 e.g.
OH PCC O
CH2Cl2
(90%) H

OH O
PCC
CH2Cl2 H
(89%)

Ch. 16 - 10
4B. Aldehydes by Ozonolysis of
Alkenes

R R" 1. O3 R R"
O + O
R' H 2. Me2S R' H

Ch. 16 - 11
  e.g.
1. O3, CH2Cl2, -78oC
O
2. Me2S
+ O
H

1. O3, CH2Cl2, -78oC O

2. Me2S
H3C H3C O
+
H H
Ch. 16 - 12
4C. Aldehydes by Reduction of Acyl
Chlorides, Esters, and Nitriles
O

R OH
or
O
O
LiAlH 4 LiAlH 4
R OR'
R H R OH
or
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 Al
R
Lithium tri- tert-butoxy Diisobutylaluminum hydride
aluminum hydride (abbreviated i-Bu2AlH or DIBAL-H)

Ch. 16 - 15
 O
1. LiAlH(OtBu)3, -78oC

R Cl 2. H2O
Acyl chloride

O o O
1. DIBAL-H, hexane, -78 C

R OR' 2. H2O R H
Ester

1. DIBAL-H, hexane
R C N
2. H2O
Nitrile Ch. 16 - 16
 Aldehydes from acyl chlorides: RCOCl
 RCHO
1. LiAlH(OtBu)3,
O O o
O
SOCl 2 Et2O, -78 C
R OH R 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 O Li
LiAlH(OtBu)3
R C R C + Al(OtBu)3
Cl Cl
H
Li
O Al(O tBu)3 O
R C H Li R C H Al(O tBu)3
Cl Cl

-LiCl
O Al(O tBu)3 O
H2O
R C R C
H 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 O Al(i-Bu)2
R C Al(i-Bu)2 R C H
OR' OR'
H

O O Al(i-Bu)2
H2O
R C R C H
H OR'

Ch. 16 - 20
 Reduction of a nitrile to an aldehyde

R C N Al( i-Bu)2 R C N Al(i-Bu)2

H
H

O N Al( i-Bu)2
H2O
R C R C
H H

Ch. 16 - 21
 Examples
O O

O 1. DIBAL-H, hexane, -78oC H

(1)
2. H2O OH

(2) C N

1. DIBAL-H, hexane, -78oC

O
2. H2O

H
Ch. 16 - 22
5. Synthesis of Ketones
5A. Ketones from Alkenes, Arenes,
o
and 2 Alcohols
 Ketones (and aldehydes) by ozonolysis
of alkenes

R R" 1. O3 R R"
O + O
R' H 2. Me2S R' H

Ch. 16 - 23
 Examples O
1. O3
(i)
2. Me2S

1. O3
(ii)
2. Me2S

O
+ O
H
Ch. 16 - 24
 Ketones from arenes by Friedel–Crafts
acylations
O
O
AlCl 3 R
+ + HCl
R Cl
an alkyl aryl
ketone

Ch. 16 - 25
 Ketones from secondary alcohols by
oxidation

OH O
H2CrO4

R R' or PCC R R'

Ch. 16 - 26
5B. Ketones from Nitriles

O
1. R'M, Et2O
R C N
2. H3O+ R R'

N M

R R'

Ch. 16 - 27
 Examples

1. MeLi, Et2O
Me
C N
2. H3O+
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
MgBr DMSO

1.
O
Et2O
N C
2. H3O+

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
MgBr O
+
H
disconnection

HO

Ch. 16 - 35
  Synthesis
PCC
HO O
MgBr
1. , Et2O

2. H3O+

O OH

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 O
C 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 O:
R'
R
R

H Nu

Nu
Nu: + C O H
R'
R
Ch. 16 - 39
 Also would expect nucleophilic addition
reactions of carbonyl compounds to be
catalyzed by acid (or Lewis acid)
H H
O O O
C + H+ C 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'
 
C O + H A
R (or a Lewis acid)

R' R'
C OH C OH + A:
R R

Ch. 16 - 41
 Mechanism

R'
C OH :Nu H
R

H + H A
Nu :Nu
C O H + A: C O H
R' R'
R 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 O
Nu
Nu
R H R
H
smal
l
O O
Nu
Nu
R R' R
R'
large
Ch. 16 - 45
 Electronic factors
(positive inductive effect from
both R & R' groups)  carbonyl
carbon less + (less
nucleophilic)
 
 
O O
C< C<
>
R  H >
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 H+ R"O OH hemi-acetal
+ R"OH (R' = H)
R R' R R' hemi-ketal
(R' = alkyl)
Catalyzed H+
by acid R"OH

acetal (R' = H) R"O OR"

ketal (R' = alkyl)
R R' Ch. 16 - 47
 Mechanism

O +
H O:
H R"
C + R"OH C + O
R R' R R' H

H
OH O
H
R O C + R"OH
R" R R'
R'
Ch. 16 - 48
 Mechanism (Cont’d) hemi-acetal (R' = H) or
hemi-ketal (R' = alkyl)
OH OH
H R"OH O
R O R OR" + R" H
R" H
R' R'

R" OH2
O
H2O + R OR"
C
R R' R'
Ch. 16 - 49
 Mechanism (Cont’d)
R"
O OR"
R"OH H
C R O
R R' R"
R'

R"OH

OR"
acetal (R' = H) or
ketal (R' = alkyl) 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" O
H+
R OR" + H2O + 2 R"OH
R' R R'

Ch. 16 - 52
 Aldehyde hydrates: gem-diols

H3C H3C O H
O + H2O
H H O H

Acetaldehyde Hydrate
(a gem-diol)

Ch. 16 - 53
  Mechanism

H3C OH2 H3C OH2 H3C OH

C O 
  H OH
H H O:

HO OH O
distillation
+ H2O
R H R H

Ch. 16 - 54
7A. Hemiacetals
H
O
O
H O
Butanal-4-ol O

OH
Hemiacetal: OH & OR groups
bonded to the same carbon A cyclic
hemiacetal
Ch. 16 - 55
 OH Hemiacetal: OH & OR
groups bonded to the
O same carbon
HO
HO OH
OH

(+)-Glucose
(A cyclic hemiacetal)

Ch. 16 - 56
7B. Acetals
OH A ketal

O
HO HO
HO O
OH
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 O O
OH
R R'
R R'
Ketone (excess) Cyclic acetal

+ H2O

Ch. 16 - 58
 This reaction, too, can be reversed by
treating the acetal with aqueous acid

H3O+ O
O O + H2O
R 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 OR" OH
No Reaction
H2O
R H

O O OH
No Reaction
H2O
R R'
 Acetals are used to protect aldehydes and
ketones from undesired reactions in basic
solutions Ch. 16 - 60
 Example

Attempt to OH
synthesize:

from: Br

Ch. 16 - 61
● Synthetic plan
O
+ BrMg

OH

 This route will not work

Ch. 16 - 62
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 , H + aqueous H+
Br OMgBr
(ketal)
O O
Mg O O
Et2O 
BrMg
 O O O

Ch. 16 - 64
7D. Thioacetals
 Aldehydes & ketones react with thiols
to form thioacetals
O 2 EtSH EtS SEt
+ H2O
R H HA R H
Thioacetal

O SH
HS S S
+ H2O
R R' BF3
R R'
Cyclic
thioacetal 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

H2, Raney Ni H H
S S + HS SH
R R'
R R'

+ 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 From a 2 amine
R3
R3
N R1 R5
N R1, R2, R3 = C or H;
R1 R2 R2 R4 R4, R5 = C
Imine Enamine
Ch. 16 - 67
 8A. Imines
o
 Addition of 1 amines to aldehydes &
ketones
R +
R
H
O + H2N R" N + H2O
R' R' R"
(1o amines)
(imines)
[(E) & (Z) isomers]

Ch. 16 - 68
 Mechanism
H
H O
O +
H3O O H
R N R"
R R' R R' H2NR" R'
H
-H+
H
OH2 O
R H
H+
N R NHR" R NHR"
R' 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 + R
H
N + H2O O + H2NR"
R' R" R'
Ch. 16 - 70
8B. Oximes and Hydrazones
o
 Imine formation – reaction with a 1 amine
R
C O + H2N R C N + H2O

aldehyde a 1o amine an imine

or ketone [(E) & (Z) isomers]

 Oxime formation – reaction with

hydroxylamine
OH
C O + H2N OH C N + H2O

aldehyde hydroxyl an oxime

or ketone amine [(E) & (Z) isomers]
Ch. 16 - 71
 Hydrazone formation – reaction with
hydrazine
NH2
C O + H2NNH2 C N + H2O

aldehyde hydrazine a hydrazone

or ketone

o
 Enamine formation – reaction with a 2
amine
O R
N R
C cat. HA
C + H N R C C + H2O
H R
2o amine enamine
Ch. 16 - 72
8C. Enamines

O R 4 R5
N
R1 cat. HA
C 3
R + H N R5 R1
H R3
R 2 R4
R2
2o amine enamine

+ H2O

Ch. 16 - 73
 Mechanism
O
O R
C
C + H N R C C N R
H R H H

H
O
C C N R
H R
aminoalcohol
intermediate
Ch. 16 - 74
 Mechanism (Cont’d)
H H H
O O
A H + C C N R C C N R
H R H R

R
N R
:A + H2O + C C
H
iminium ion
intermediate
Ch. 16 - 75
 Mechanism (Cont’d)

R
R
N R N
C C C C R + H A
H H

A: enamine

Ch. 16 - 76
9. The Addition of Hydrogen
Cyanide: Cyanohydrins
 Addition of HCN to aldehydes & ketones

O OH
HCN

R R' R CN
R' (cyanohydrin)

CN O
H+
R CN
R'
Ch. 16 - 77
 Mechanism

O O
CN

R R' R CN
(slow)
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 O Na OH

NaCN R R' H2SO4 R CN

R R'
CN R'

Ch. 16 - 79
  Synthetic applications
HCl, H2O HO COOH
R
heat R'
(-hydroxy acid)

O CN COOH
HCN HO 95% H2SO4
R R R
R' R' heat R'
(,-unsaturated acid)

1. LiAlH4 HO NH2
R
2. H2O R'
(-aminoalcohol)

Ch. 16 - 80
10. The Addition of Ylides: The
Wittig Reaction
R R" R R"
O + (C6H5)3P C C C
R' R" R' R"
aldehyde phosphorus ylide alkene
or ketone (or phosphorane) [(E) & (Z) isomers]
+
O P(C6H5)3

triphenyl-
phosphine
oxide
Ch. 16 - 81
 Phosphorus ylides
R" R"
(C6H5)3P C (C6H5)3P C
R" R"
R" R"
(C6H5)3P: + CH X (C6H5)3P CH X
R"' R"'
triphenyl- an alkyltriphenylphos-
phosphine phonium halide

R" R"
(C6H5)3P C H :B (C6H5)3P C + H:B
R"' R"'
a phosphorus
ylide Ch. 16 - 82
  Example
C6H6
(C6H5)3P: + CH3Br (C6H5)3P CH3 Br

Methyltriphenylphos-
phonium bromide
(89%)

(C6H5)3P CH3 + C6H5Li (C6H5)3P CH2:

Br + C6H6 + LiBr

Ch. 16 - 83
 Mechanism of the Wittig reaction
R" R' R"
R R'
C + :C R"' R C C R"'
:O: P(C6H5)3 :O P(C6H5)3

:
aldehyde ylide oxaphosphetane
or ketone

R' R"
: :

O P(C6H5)3 + C C
R R"
triphenylphosphine alkene
oxide (+ diastereomer) Ch. 16 - 84
10A. How to Plan a Witting Synthesis

 Synthesis of

using a Wittig reaction

Ch. 16 - 85
 Retrosynthetic analysis
O
route 1
+ Ph3P
disconnection

route 2 Ph3P: + Br

PPh3
+ O

Br
+ :PPh3
Ch. 16 - 86
 Synthesis – Route 1

:PPh 3
Br Ph3P Br

n
BuLi
O

Ph3P

Ch. 16 - 87
 Synthesis – Route 2

Br PPh3 Br
:PPh 3

n
BuLi

PPh3
O

Ch. 16 - 88
10B. The Horner–Wadsworth–Emmons
Reaction

O NaH O
P OEt P OEt
OEt OEt

a phosphonate
ester + H2

Ch. 16 - 89
 O

O H
+
P OEt
OEt

O
+
EtO P O Na
EtO
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
+ P
X EtO OEt
Triethyl phosphite

O
EtX +
P OEt
OEt
Ch. 16 - 91
11. Oxidation of Aldehydes
O KMnO4, OH O

or Ag2O, OH
R H R O

+
H3O

R OH

Ch. 16 - 92
12. Chemical Analyses for Aldehydes
and Ketones
12A. Derivatives of Aldehydes & Ketones
R H
O + H2N N NO2
R' hydrazine
O2N
R
 N
H
R' N NO2
H
hydrazone
(orange ppt.) O2N Ch. 16 - 93
12B. Tollens’ Test (Silver Mirror Test)

O Ag(NH 3)2 O
+ Ag
R H H2O R O
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 CHO 1720 - 1740 RCOR 1705 - 1720
Ar CHO 1695 - 1715 ArCOR 1680 - 1700

C C 1680 - 1690 C C 1665 - 1680

CHO 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
 13CNMR 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

R OH
N
R2NH 1. RM R
H + 2. H3O+
R-NH2, H+ O
OH
RO OR 1. LiAlH4 or NaBH4
+ + H
2 ROH, H 2. H3O

R 1. NaCN OH
R PPh3
2. H3O+ CN

Ch. 16 - 102
 END OF CHAPTER 16 

Ch. 16 - 103