Chapter 16

Aldehydes and Ketones

1. Introduction

❖ Carbonyl compounds
O O O

R H R R' R OR'
aldehyde ketone ester

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

aryl groups)
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,
starting at the carbonyl carbon
❖ 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
 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
 CO2H O

2-Methanoylbenzoic acid SO3H

(o-formylbenzoic acid)

O
4-Ethanoylbenzenesulfonic acid
(p-acetylbenzenesulfonic acid)
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)
4. Synthesis of Aldehydes
o
4A. Aldehydes by Oxidation of 1 Alcohols

Pyridinium chlorochromate (PCC)

❖ e.g.
OH PCC O
CH2Cl2
(90%) H

OH O
PCC
CH2Cl2 H
(89%)
4B. Aldehydes by Ozonolysis of
Alkenes
 ❖ e.g.
1. O3, CH2Cl2, -78oC
O
2. Me2S
+ O
H

1. O3, CH2Cl2, -78oC O

2. Me2S
H3C H3C O
+
H H
4C. Aldehydes by Reduction of Acyl
Chlorides, and Esters
❖ 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
❖ Two aluminum hydride derivatives that
are less reactive than LAH:
 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
❖ Aldehydes from acyl chlorides: RCOCl
→ RCHO
1. LiAlH(OtBu)3,
O O o
O
SOCl2 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
❖ Examples
5. Synthesis of Ketones
5A. Ketones from Alkenes, Arenes,
o
and 2 Alcohols
❖ Ketones (and aldehydes) by ozonolysis
of alkenes
❖ Examples O
1. O3
(i)
2. Me2S

O
❖ Aryl ketones from arenes by Friedel–
Crafts acylations
O

O
AlCl 3 R
+ + HCl
R Cl
an alkyl aryl
ketone
❖ Ketones from secondary alcohols by
oxidation

OH O
H2CrO4

R R' or PCC R R'

Swern Oxidation

Swern oxidation of a 1°
alcohol to an aldehyde

Swern oxidation of a 2°
alcohol to a ketone
5B. Ketones from Nitriles

O
1. R'−M, Et2O
R C N
2. H3O+ R R'

N M

R R'
❖ Examples
❖ Suggest synthesis of
O

Br
from and HO
❖ Retrosynthetic analysis
O

HO

5 carbons here 4 carbons here

 need to add
one carbon
❖ Retrosynthetic analysis
disconnection

disconnection

NC +

Br

HO
❖ Synthesis

PBr3
HO Br

NaCN
MgBr DMSO

1.
O
Et2O
N C
2. H3O+
❖ Suggest synthesis of
O

Br
from and HO
❖ Retrosynthetic analysis
O

HO

5 carbons here
5 carbons here

 no need to
add carbon
❖ Retrosynthetic analysis

MgBr O
+
H
disconnection

HO
❖ Synthesis
6. Nucleophilic Addition to the
Carbon–Oxygen Double Bond
❖ Structure

⊖
Nu

● Carbonyl carbon: sp2 hybridized

● Trigonal planar structure
❖ Polarization and resonance structure
−
O O
C C
+

● Nucleophiles will attack the

electrophilic carbonyl carbon

● Note: nucleophiles usually do not

attack a non-polarized C=C bond
❖ With a strong nucleophile:

R' + − Nu
 
Nu: C O C O:
R'
R
R

H Nu

Nu
Nu: + C O H
R'
R
❖ catalyzed by an acid (or Lewis acid)

● Note: full positive charge on the carbonyl

carbon in one of the resonance forms
⧫ Nucleophiles readily attack
❖ Mechanism
R'
+ −
C O + H A
R (or a Lewis acid)

R' R'
C OH C OH + A:
R R
❖ Mechanism

R'
C OH :Nu H
R

H + H A
Nu :Nu
C O H + A: C O H
R' R'
R R
6B. Relative Reactivity: Aldehydes,
Ketones, and Esters

O O O
> >
R H R R' R OR'

Why?
Again……again and again……………..
❖ Steric factors
O O
Nu
Nu
R H R
H
small

O O
Nu
Nu
R R' R
R'
large
❖ Electronic factors
(positive inductive effect from
both R & R' groups)  carbonyl
carbon less + (less nucleophilic)

(positive inductive
effect from only
one R group)
6C. Addition Products Can Undergo
Further Reactions

stable product: isolable

❖ But

unstable
7. The Addition of Alcohols:
Hemiacetals and Acetals
❖ Hemiacetal & Acetal 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'
❖ 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"
❖ 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'
❖ 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'
❖ Note: All steps are reversible. In the
presence of a large excess of
anhydrous alcohol and a 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, the acetal or ketal will
hydrolyze back to aldehyde or ketone.
This process is called hydrolysis.
❖ 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'
❖ Aldehyde hydrates: gem-diols

H3C H3C O H
O + H2O
H H O H

Acetaldehyde Hydrate
(a gem-diol)
 ❖ Mechanism

H3C OH2 H3C OH2 H3C OH

C+ O −
  H OH
H H O:

HO OH O
distillation
+ H2O
R H R H
7A. Hemiacetals
H
O
O
H O
Butanal-4-ol O

OH
Hemiacetal: OH & OR groups
bonded to the same carbon A cyclic
hemiacetal
 OH Hemiacetal: OH & OR
groups bonded to the
O same carbon
HO
HO OH
OH

(+)-Glucose
(A cyclic hemiacetal)
7B. Acetals
OH A ketal

O
HO HO
HO O
OH
O HO
OH
An acetal OH

Sucrose
(table sugar)
❖ 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
❖ This reaction, too, can be reversed by
treating the acetal with lots of an
aqueous acid

H3O+ O
O O + H2O
R R'
R R'
+

HO
OH
7C. Acetals Are Used as Protecting
Groups
❖ Although acetals are hydrolyzed to aldehydes
and ketones in aqueous acid, acetals are
stable in basic solutions
❖ Acetals are used to protect aldehydes
and ketones from undesired reactions
in basic solutions
❖ Example

Attempt to OH
synthesize:

from: Br

O
● Synthetic plan
O
+ BrMg

OH

⧫ This route will not work

Reason:
(a) Intramolecular nucleophilic addition
O
+ −
BrMg

(b) Homodimerization or polymerization

O

BrMg O

BrMg O

BrMg
⧫ Thus, need to “protect” carbonyl group first

OH
HO , H+
Br OMgBr
(ketal)
O O
Mg O O
Et2O +
BrMg
− O O O
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
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
8A. Imines
o
❖ Addition of 1 amines to aldehydes &
ketones
❖ Mechanism H
H O
O +
H3O O H
R N R"
R R' R R' H2NR" R'
H
-H+
H
OH2 O
H+
R NHR" R NHR"
R' R'
(amino alcohol)
H2O
❖ Similar to the formation of acetals and
ketals, all the steps in the formation of
imines are reversible.

❖ Hydrolysis of imines is also possible by

adding excess water in the presence of
catalytic amount of acid
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]
❖ Hydrazone formation – reaction with
hydrazine
NH2
C O + H2NNH 2 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
8D. Enamines
❖ Mechanism
O
O R
C
C + H N R C C N R
H R H H
❖ 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
❖ Mechanism (Cont’d)

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

A: enamine
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'
❖ Mechanism

O O
CN

R R' R CN
(slow)
R'

NC H

OH

R CN
R'
 ❖ 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)
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(C 6H5)3

triphenyl-
phosphine
oxide
❖ Phosphorus ylides
R" R"
(C6H5)3P C (C6H5)3P C
R" R"

R" R"
(C6H5)3P C H :B (C6H5)3P C + H:B
R"' R"'
a phosphorus
ylide
 ❖ Example
C6H6
(C6H5)3P: + CH3Br (C6H5)3P CH3 Br

Methyltriphenylphos-
phonium bromide
(89%)

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

Br + C6H6 + LiBr
❖ Mechanism of the Wittig reaction
R" R' R"
R R'
C + :C R"' R C C R"'
:O: P(C 6H5)3 :O P(C 6H5)3

:
aldehyde ylide oxaphosphetane
or ketone

R' R"
: :

O P(C 6H5)3 + C C
R R"
triphenylphosphine alkene
oxide (+ diastereomer)
10A. How to Plan a Wittig Synthesis

❖ Synthesis of

using a Wittig reaction

❖ Retrosynthetic analysis
O
route 1
+ Ph3P
disconnection

route 2 Ph3P: + Br

PPh 3
+ O

Br
+ :PPh3
❖ Synthesis – Route 1

:PPh 3
Br Ph3P Br

n
BuLi
O

Ph3P
❖ Synthesis – Route 2
11. Oxidation of Aldehydes
12. The Baeyer-Villiger Oxidation
13. Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
❖ 1,2-addition: Addition of a nucleophile
directly to the carbonyl group
● Grignards; Organolithiums, NaBH4, LiAlH4.
13. Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
❖ Conjugate addition (1,4-addition): Addition of a
nucleophile to the C=C double bond
● Cyanide, 1 ̊ & 2 ̊ amines, enolates and enamines.
❖ Organocopper Reactions
● Reaction of an -unsaturated ketone with a
Gillman reagent
15. Spectroscopic Properties of
Aldehydes and Ketones
15A. IR Spectra of Aldehydes and Ketones
15B. 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
❖ 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
16. Summary of Aldehyde and
Ketone Addition Reactions
NR2

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

R 1. NaCN OH
R PPh 3
2. H3O+ CN