Chapter 17

Aldehydes and Ketones.

Nucleophilic Addition
to the Carbonyl Group

1
17.1. IUPAC Nomenclature of Aldehydes
O O

H H

4,4-dimethylpentanal 5-hexenal

O O
Base the name on the HCCHCH
chain that contains the
carbonyl group and 2-phenylpropanedial
replace the -e ending of (keep the -e ending
the hydrocarbon by -al. before -dial) 2
IUPAC Nomenclature of Aldehydes

when named as C H when named

a substituent as a suffix

formyl group carbaldehyde or

carboxaldehyde

3
Substitutive IUPAC Nomenclature of Ketones
O O

CH3CH2CCH2CH2CH3 CH3CHCH2CCH3

CH3
3-hexanone 4-methyl-2-pentanone

¾ Base the name on the

chain that contains the
carbonyl group and replace -
H3C O
e by -one. Number the
chain in the direction that 4-methylcyclohexanone
gives the lowest number to
4
the carbonyl carbon.
 Functional Class IUPAC Nomenclature of Ketones

O O
CH3CH2CCH2CH2CH3 PhCH2CCH2CH3
ethyl propyl ketone benzyl ethyl ketone

¾ List the groups attached O

to the carbonyl separately
in alphabetical order, and H2C CHC CH CH2
add the word ketone. divinyl ketone
5
17.2. Structure and Bonding: The Carbonyl Group

Structure of Formaldehyde

- Planar
- Bond angles: close to 120°
- C=O bond distance: 122 pm
6
 The Carbonyl Group

very polar double bond

1-butene Propanal

dipole moment = 0.3D dipole moment = 2.5D

7
 Carbonyl group of a ketone is more
stable than that of an aldehyde

O heat of combustion
2475 kJ/mol
H

2442 kJ/mol
O
Alkyl groups stabilize carbonyl groups the same way
they stabilize carbon-carbon double bonds,
carbocations, and free radicals. 8
 Spread is greater for aldehydes and
ketones than for alkenes

O Heats of combustion of
C4H8 isomeric alkenes
H CH3CH2CH=CH2
2475 kJ/mol 2717 kJ/mol
cis-CH3CH=CHCH3
2710 kJ/mol

O trans-CH3CH=CHCH3
2707 kJ/mol
2442 kJ/mol
(CH3)2C=CH2
2700 kJ/mol 9
Resonance Description of
Carbonyl Group

•• •• –
O •• •• O ••

C C
+
nucleophiles attack carbon;
electrophiles attack oxygen

10
 Bonding in Formaldehyde

Carbon and oxygen The half-filled p

are sp2 hybridized orbitals on carbon
and oxygen overlap
to form a π bond

11
 17.3. Physical Properties

Aldehydes and ketones have higher boiling than

alkenes, but lower boiling points than alcohols.

boiling point

–6° C
More polar than
alkenes, but cannot
O 49°C form intermolecular
hydrogen bonds to
other carbonyl groups.
OH 97°C 12
17.4. Sources of Aldehydes and Ketones

Many aldehydes and ketones occur naturally

O O

H
2-heptanone trans-2-hexenal
(component of alarm (alarm pheromone of
pheromone of bees) myrmicine ant)

H
citral (from lemon grass oil) 13
 Synthesis of Aldehydes and Ketones

• From alkenes

A number of – ozonolysis
reactions already • From alkynes
studied provide
efficient synthetic – hydration (via enol)
routes to • From arenes
aldehydes and
ketones. – Friedel-Crafts acylation
• From alcohols
– oxidation 14
 What about..?

Aldehydes from carboxylic acids

O O

C C
R OH R H

1. LiAlH4 PDC, CH2Cl2

2. H2O RCH2OH

15
 Example

Benzaldehyde from benzoic acid

O O

COH CH

1. LiAlH4 PDC
2. H2O CH2Cl2
CH2OH
(81%) (83%)

16
 What about..?
Ketones from aldehydes

O O

C C
R H R R'

1. R'MgX OH
PDC, CH2Cl2
2. H3O+
RCHR'

17
 Example
3-Heptanone from propanal

O O

C CH3CH2C(CH2)3 CH3
CH3CH2 H
(57%)
1. CH3(CH2)3MgX
H2CrO4
2. H 3 O+ OH

CH3CH2CH(CH2)3 CH3

18
 17.5. Reactions of Aldehydes and
Ketones: A Review and a Preview

¾ Already covered in earlier chapters:

¾ Reduction of C=O to CH2

– Clemmensen reduction

– Wolff-Kishner reduction

¾ Reduction of C=O to CHOH

¾ Addition of Grignard and organolithium reagents.

19
 17.6. Principles of Nucleophilic Addition to
Carbonyl Groups: Hydration of Aldehydes and
Ketones

C O ••
••

H2O

•• ••
HO C O H
•• ••
20
Substituent Effects on Hydration Equilibria

O OH

C + H2O R C R'
R R'
OH

compared to H

Electronic: alkyl groups stabilize reactants

Steric: alkyl groups crowd product

21
Equilibrium Constants and Relative Rates
of Hydration
C=O hydrate K % Relative
rate

CH2=O CH2(OH)2 2300 >99.9 2200

CH3CH=O CH3CH(OH)2 1.0 50 1.0

(CH3)3CCH=O (CH3)3CCH(OH)2 0.2 17 0.09

(CH3)2C=O (CH3)2C(OH)2 0.0014 0.14 0.0018

22
When does equilibrium favor hydrate?

When carbonyl group is destabilized,

- alkyl groups stabilize C=O

- electron-withdrawing groups destabilize C=O

23
Substituent Effects on Hydration Equilibria

O OH

C + H2O R C R'
R R'
OH

R = CH3: K = 0.000025
R = CF3: K = 22,000

24
 Mechanism of Hydration (base)

Step 1:

H
• O •– •• •• •–
• •• • + C O •• HO C O•
•• •• ••

25
 Mechanism of Hydration (base)

Step 2:

•• •• •–
HO C O•
•• ••

H
H
•• •• – H O ••
HO C OH •
+ •• O •• ••
•• •• ••
26
 Mechanism of Hydration (acid)

Step 1:
H
C O •• + H O ••
•• +
H

H
+
C OH + •O•
• •
••
H
27
 Mechanism of Hydration (acid)

Step 2:

H H
+ ••
•O• + C OH •O C OH
• • • +
•• ••
H H
28
 Mechanism of Hydration (acid)

Step 3:
H •• H
+O H •• H
O
H ••

+ H
••
•O C OH
•• •• • +
•O ••
• C OH
•• H
H 29
 17.7. Cyanohydrin Formation

•N ••
C O •• + HCN • C C O
•• H
••

•N •– C O ••
• C•
••

•• –
•N
• C C O ••
•• 30
 Cyanohydrin Formation

•• – H O ••
•N
• C C O •• +
••
H

H
•• • O ••
•N C C O H •
•
••
H 31
 Example

Cl Cl
O 1. NaCN, OH
water
Cl CH Cl CHCN
2. H2SO4

2,4-Dichlorobenzaldehyde
cyanohydrin (100%)

32
 Example

O OH
1. NaCN, water
CH3CCH3 CH3CCH3
2. H2SO4
CN
(77-78%)

Acetone cyanohydrin is used in the synthesis of

methacrylonitrile
33
 17.8. Acetal Formation

Some reactions of aldehydes and ketones

progress beyond the nucleophilic addition stage

- Acetal formation

- Imine formation

- Enamine formation

- Compounds related to imines

- The Wittig reaction

34
Recall Hydration of Aldehydes and Ketones

R
C O ••
••
R'

HOH

R
•• ••
HO C O H
•• ••
R' 35
Alcohols Under Analogous Reaction
with Aldehydes and Ketones

R
C O ••
••
R'

R"OH Product is called

a hemiacetal.
R
••
••
R"O C O H
•• ••
36
R'
Hemiacetal reacts further in acid to yield
an acetal
R
•• •• Product is called
R"O C OR
•• •• an acetal.
R'

ROH, H+

R
•• ••
R"O C O H Product is called
•• •• a hemiacetal.
R' 37
 Example
O

CH + 2CH3CH2OH

HCl

CH(OCH2CH3)2 + H2O

Benzaldehyde diethyl acetal (66%)

38
 Diols Form Cyclic Acetals

CH3(CH2)5CH + HOCH2CH2OH
benzene
p-toluenesulfonic acid
H2C CH2

O O + H2O
C
(81%) H (CH2)5CH3
39
 In general:

¾ Position of equilibrium is usually unfavorable for

acetal formation from ketones.

¾ Important exception: Cyclic acetals can be

prepared from ketones.

40
 Example

C6H5CH2CCH3 + HOCH2CH2OH
benzene
p-toluenesulfonic acid
H2C CH2

O O + H2O
(78%) C
C6H5CH2 CH3
41
 Mechanism of Acetal Formation

¾ First stage is analogous to hydration and leads

to hemiacetal
¾ Acid-catalyzed nucleophilic addition of alcohol to
C=O

42
 Mechanism
H
••
C O•• H O ••
+
R

H
•• +
C O •• O ••
H
R
43
R
•• +
•• O •• C O
H H

R R
•• •• •• ••
O C O •• O C O ••
+ ••
H H H

H
••
O +
R •• H O
R •• H
44
 Mechanism of Acetal Formation
¾ Second stage is hemiacetal-to-acetal conversion.
¾ Involves carbocation chemistry.

H
R
•• ••
O C O •• H O ••
••
•• +
H R

H
R H
•• •• •• O ••
O C O+
••
••
H R 45
 Hemiacetal-to-acetal Stage

R H R H
•• •• •• ••
O C O+ O C+ •• O
••
•• ••
••
H H

R R
•• +
O C+ O C
•• ••

Carbocation is stabilized by delocalization of unshared

electron pair of oxygen
46
 Hemiacetal-to-acetal Stage
R R
•• ••
O C+ •• O
••
H
R R
R R •• ••
•• ••
O C O
•• ••
O C O+
••
H R
R ••
•• H O
•• O +
H 47
H
 Hydrolysis of Acetals

OR" O

R C R' + H2O C + 2R"OH

R R'
OR"

¾ Mechanism:
reverse of acetal formation; hemiacetal is
intermediate
¾ Application:
aldehydes and ketones can be "protected" as
acetals.
48
 17.9. Acetals as Protecting Groups
Example
The conversion shown cannot be carried out directly...

O O
1. NaNH2
CH3CCH2CH2C CH CH3CCH2CH2C CCH3
2. CH3I

O
–
CH3CCH2CH2C C:

because the carbonyl group and the carbanion are

incompatible functional groups. 49
 Strategy

1) Protect C=O
2) Alkylate
3) Restore C=O

50
 Example: Protect
O

CH3CCH2CH2C CH + HOCH2CH2OH
benzene
p-toluenesulfonic acid

H2C CH2

O O
C
CH3 CH2CH2C CH
51
 Example: Alkylate
H2C CH2

O O
C
CH3 CH2CH2C CCH3

H2C CH2
1. NaNH2
O O
2. CH3I
C
CH3 CH2CH2C CH
52
 Example: Deprotect
H2C CH2

O O H2O
C HCl
CH3 CH2CH2C CCH3

HOCH2CH2OH + CH3CCH2CH2C CCH3

(96%)
53
 17.10. Reaction with
Primary Amines: Imines

Some reactions of aldehydes and ketones progress

beyond the nucleophilic addition stage

¾ Acetal formation
¾ Imine formation
¾ Compounds related to imines
¾ Enamines
¾ The Wittig reaction
54
 Imine (Schiff's Base) Formation

•• ••
H2N •• + C O •• HN C O H
•• ••
R R
a carbinolamine

••
N C (imine) + H2O
R
55
 Example

CH + CH3NH2 OH

CH

NHCH3
CH=NCH3 + H2O

N-Benzylidenemethylamine (70%)
56
 Example

O + (CH3)2CHCH2NH2

OH
NHCH2CH(CH3)2

NCH2CH(CH3)2 + H2O

N-Cyclohexylideneisobutylamine
(79%) 57
 Compounds Related to Imines
Reaction with Derivatives of Ammonia

H2N G + R2C O R2C NG + H2O

H2N OH R2C NOH

hydroxylamine oxime

58
 Example
O

CH3(CH2)5CH + H2NOH

NOH

CH3(CH2)5CH + H2O

(81-93%) 59
 Reaction with Derivatives of Ammonia

H2N G + R2C O R2C NG + H2O

H2N OH R2C NOH

hydroxylamine oxime

H2N NH2 R2C NNH2

hydrazine hydrazone

etc. 60
Example

C + H2NNH2

NNH2

C + H2O

61
(73%)
 Example

CCH3 + H2NNH

phenylhydrazine

NNH

CCH3 + H2O

a phenylhydrazone (87-91%) 62
 Example

O O

CH3(CH2)9CCH3 + H2NNHCNH2

semicarbazide

NNHCNH2

CH3(CH2)9CCH3 + H2O
a semicarbazone (93%) 63
 17.11. Reaction with Secondary Amines:
Enamine Formation

H C H C
•• •• ••
R2NH C O •• R2N C O H
•• ••

C
••
R2N C + H2O

(enamine) 64
 Example
O

+ (heat in benzene) N
N
H

(80-90%)
N OH
via

65
 17. 12. The Wittig Reaction
¾ Synthetic method for preparing alkenes.
¾ One of the reactants is an aldehyde or ketone.
¾ The other reactant is a phosphorus ylide.

A A
+ –
(C6H5)3P C •• (C6H5)3P C
B B

¾ A key property of ylides is that they have a negatively

polarized carbon and are nucleophilic.
66
Figure 17.12. Charge distribution in a ylide

67
 The Wittig Reaction

R A
•• + –
C O + (C6H5)3P C ••
••
R' B

R A
+ •• –
C C + (C6H5)3P O ••
••
R' B
68
 Example
•• + –
O + (C6H5)3P CH2
•• ••

DMSO

+ •• –
CH2 + (C6H5)3P O ••
••
(86%)

¾ Dimethyl sulfoxide (DMSO) or tetrahydrofuran

(THF) is the customary solvent 69
 Mechanism

Step 1

R R
•• ••
C O R' C O ••
••
R'
A A C P(C6H5)3
•• +
C P(C6H5)3 B
–
B Oxaphosphetane
70
 Mechanism

Step 2

R
R ••
R' •• – C O ••
•• O •• R'
C
+
C P(C6H5)3 A C P(C6H5)3
+
A B
B

71
 17.13
Planning an Alkene Synthesis via
the Wittig Reaction

72
 Retrosynthetic Analysis
R A
C C
R' B

¾ There will be two possible Wittig routes to an alkene.

¾ Analyze the structure retrosynthetically.
¾ Disconnect the doubly bonded carbons. One will
come from the aldehyde or ketone, the other from the
ylide.
73
 Retrosynthetic Analysis of Styrene
O
+ –
C6H5CH + (C6H5)3P CH2
••

Both routes
C6H5CH CH2 are acceptable.

O
+ –
(C6H5)3P CHC6H5 + HCH 74
••
 Preparation of Ylides
¾ Ylides are prepared from alkyl halides by a two-
stage process.
¾ The first step is a nucleophilic substitution.
Triphenylphosphine is the nucleophile

A
A +
(C6H5)3P •• + CH X (C6H5)3P CH
B
B

+ X–
75
 Preparation of Ylides
¾ In the second step, the phosphonium salt is treated
with a strong base in order to remove a proton from the
carbon bonded to phosphorus

A A
+ – +
(C6H5)3P C •• (C6H5)3P C H
B B

base H –
base ••

76
 Preparation of Ylides
¾ Typical strong bases include organolithium
reagents (RLi), and the conjugate base of dimethyl
sulfoxide as its sodium salt [NaCH2S(O)CH3].

A A
+ – +
(C6H5)3P C •• (C6H5)3P C H
B
B

base H –•
base •
77
 17.14
Stereoselective Addition to
Carbonyl Groups

Nucleophilic addition to carbonyl

groups sometimes leads to a mixture
of stereoisomeric products.

78
Example H3C CH3

H3C CH3 H3C CH3

NaBH4

OH H

H OH

80% 20% 79
Steric Hindrance to Approach of Reagent

this methyl group hinders

approach of nucleophile
from top

–
H3B—H
preferred direction of approach
is to less hindered (bottom) face
80
of carbonyl group
Biological reductions are highly stereoselective

pyruvic acid → S-(+)-lactic acid

CO2H
O
NADH HO
CH3CCO2H H
H+
CH3

enzyme is lactate dehydrogenase

81
Figure 17.14

¾ One face of the

substrate can bind to the
enzyme better than the
other.

¾ Change in geometry from

trigonal to tetrahedral is
stereoselective. Bond formation
occurs preferentially from one
side rather than the other.
82
17.15. Oxidation of Aldehydes

O OH O
H2O
RCH RCH RCOH

OH

in aqueous solution

83
 Example

O K2Cr2O7 O

O CH H2SO4 O COH
H2O
(75%)

OH
via
O CH

OH 84
17.16. Baeyer-Villiger Oxidation of Ketones

Oxidation of ketones with peroxy acids

gives esters by a novel rearrangement.

General

O O O O

RCR' + R"COOH ROCR' + R"COH

Ketone Ester
85
 Example

O
O O
C6H5COOH
CCH3 OCCH3
CHCl3

(67%)

¾ Oxygen insertion occurs between carbonyl carbon

and larger group.
¾ Methyl ketones give acetate esters
86
 Stereochemistry

O
O O
C6H5COOH
H3C CCH3 H3C OCCH3
CHCl3
H H H H
(66%)

¾ Reaction is stereospecific. Oxygen insertion occurs

with retention of configuration.

87
 Mechanism
O O O O

RCR' + R"COOH ROCR' + R"COH

O H
¾ First step is nucleophilic
addition of peroxy acid R C R'
to the carbonyl group of
the ketone. O OCR"
¾ Second step is
migration of group R from
carbon to oxygen. The O
weak O—O bond breaks
in this step. 88
 Biological Baeyer-Villliger Oxidation
O2.
cyclohexanone
bacterial O monooxygenase,
O
oxidation coenzymes O

¾ Certain bacteria use hydrocarbons as a source of

carbon. Oxidation proceeds via ketones, which then
undergo oxidation of the Baeyer-Villiger type.
89
 Section 17.17
Spectroscopic Analysis of
Aldehydes and Ketones

90
 Infrared Spectroscopy

¾ Presence of a C=O group is readily apparent in

infrared spectrum
¾ C=O stretching gives an intense absorption at
1710-1750 cm-1.
¾ In addition to peak for C=O, aldehydes give two
weak peaks near 2720 and 2820 nm for H—C=O

91
Figure 17.16: Infrared Spectrum of Butanal

2820 cm-1
2720 cm-1

H—C=O

CH3CH2CH2CH=O
1720 cm-1
C=O

3500 3000 2500 2000 1500 1000 500

Wave number, cm-1
92
 1H NMR

¾ Aldehydes: H—C=O proton is at very low field (δ

9-10 ppm).

¾ Methyl ketones: CH3 singlet near δ 2 ppm.

93
 O
H C CH(CH3)2

10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

Chemical shift (δ, ppm) 94

 O

CH3CH2 C CH3

10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

Chemical shift (δ, ppm) 95

 13C NMR
¾ Carbonyl carbon is at extremely low field-near δ 200 ppm.
¾ Intensity of carbonyl carbon is usually weak.

CH3CH2CCH2CH2CH2CH3

200 180 160 140 120 100 80 60 40 20 0

96
Chemical shift (δ, ppm)
 UV-VIS
¾ Aldehydes and ketones have two bands in the UV
region:
π → π* and n → π*
π → π*: excitation of a bonding π electron to an
antibonding π * orbital
n → π*: excitation of a nonbonding electron on
oxygen to an antibonding π * orbital n

H3C
•• π → π* λmax 187 nm
C O ••
n → π* λmax 270 nm
H3C 97
 Mass Spectrometry

¾ Molecular ion fragments to give an acyl cation

•+
O ••
m/z 86
CH3CH2CCH2CH3

+
CH3CH2C O •• + • CH2CH3

m/z 57
98