SENYAWA GUGUS KARBONIL

Aldehydes and Ketones

 The Carbonyl Group

• In the remainder of the course, we will study

the physical and chemical properties of classes
of compounds containing the carbonyl C=O group.
– aldehydes and ketones (Chapter 16)
– carboxylic acids
– acid halides, acid anhydrides, esters, amides
 The Carbonyl Group
– The carbonyl group consists of one sigma
bond formed by the overlap of sp2 hybrid
orbitals and one pi bond formed by the
overlap of parallel 2p orbitals
– pi bonding and pi antibonding MOs for
formaldehyde
 Structure
– The functional group of an aldehyde is a
carbonyl group bonded to an H atom and a
carbon atom.
– The functional group of a ketone is a carbonyl
group bonded to two carbon atoms.
O O O
HCH CH3 CH CH3 CCH3
Methanal Ethanal Propanone
(Formaldehyde) (Acetaldehyde) (Acetone)
 Nomenclature
• IUPAC names:
– The parent chain is the longest chain that
contains the carbonyl group.
– For an aldehyde, change the suffix from -e
to -al.
-al
– For an unsaturated aldehyde, change the
infix from -an- to -en-;
-en- the location of
the suffix determines the numbering
pattern.
– For a cyclic molecule in which -CHO is
bonded to the ring, add the suffix
-carbaldehyde.
carbaldehyde
 Nomenclature: Aldehydes
O O O
7 5 3 1
H H 8 6 4 2
H

3-Methylbutanal 2-Propenal (2E)-3,7-Dimethyl-2,6-octadienal

(Acrolein) (Geranial)

4 1
CHO HO CHO
Cyclopentane- trans-4-Hydroxycyclo-
carbaldehyde hexanecarbaldehyde

– The IUPAC naming uses the common names

benzaldehyde, cinnamaldehyde, formaldehyde
and acetaldehyde.
CHO
CHO C6 H5

Benzaldehyde trans-3-Phenyl-2-propenal
(Cinnamaldehyde)
 Nomenclature: Ketones
IUPAC names
• The parent alkane is the longest chain that
contains the carbonyl group.
• For a ketone, change the suffix -e to -one.
-one
• Number the chain to give C=O the smaller
number.
• IUPAC uses the common names acetone,
acetophenone, and benzophenone.
O O O
O

Propanone Acetophenone Benzophenone 1-Phenyl-1-pentanone

(Acetone)
 Order of Precedence
For compounds containing more than one
functional group usually indicated by a suffix:
 Common Names
• For an aldehyde, the common name is derived
from the common name of the corresponding
carboxylic acid.
• For a ketone, name the two alkyl or aryl groups
bonded to the carbonyl carbon and add the
word ketone.

O O O O
HCH HCOH CH3 CH CH3 COH
Formaldehyde Formic acid Acetaldehyde Acetic acid
O
O O

Ethyl isopropyl ketone Diethyl ketone Dicyclohexyl ketone

 Physical Properties
• Oxygen is more electronegative than
carbon (3.5 vs 2.5) and, therefore, a C=O
group is polar.
+ - + –
C O C O C O

Polarity of More important

a carbonyl contributing
group structure

Aldehydes and ketones are polar compounds and

interact in the pure state by dipole-dipole interaction.
They have higher boiling points and are more
soluble in water than nonpolar compounds of
comparable molecular weight.
 Reaction Themes
• One of the most common reaction
themes of a carbonyl group is addition
of a nucleophile to form a tetrahedral
carbonyl addition compound.

-
R O
-
Nu + C O Nu C
R R
R
Tetrahedral carbonyl
addition compound
 Reaction Themes
• A second common theme is reaction with a
proton or other Lewis acid to form a
resonance-stabilized cation.
– Protonation increases the electron
deficiency of the carbonyl carbon and makes
it more reactive toward nucleophiles.

R fast R + R
- +
C O + H- B B + C O H C O H
R R R

R O-H
- + slow
B + H- Nu + C O H Nu C + H- B
R R
R
 Reaction Themes
• Often the addition to a carbonyl group will
produce a new stereocenter.
• If none of the starting materials is chiral and
the reaction takes place in an achiral
environment, a racemic mixture will be formed.
Approach from
the top face Nu Nu
O OH
R R
- R R' H3 O + R'
Nu C O + +
R' R R
R' R'
O OH
Nu Nu
Approach from A new chiral A racemic mixture
the bottom face center is created
 Addition of C Nucleophiles
Addition of carbon nucleophiles is one of the
most important types of nucleophilic additions
to a C=O group.
• A new carbon-carbon bond is formed in the
process.
• Four common types of carbon nucleophiles are:

RMgX RLi RC C - -
C N
A Grignard An organolithium An alkyne Cyanide ion
reagent reagent anion
 Grignard Reagents

• Given the difference in electronegativity

between carbon and magnesium (2.5 - 1.3),
the C-Mg bond is polar covalent, with Cδ- and
Mgδ +.
– A Grignard reagent behaves as a
carbanion.
• Carbanion: An anion in which carbon has an
unshared pair of electrons and bears a
negative charge.
– A carbanion is a good nucleophile and adds
readily to the carbonyl group of aldehydes
and ketones.
 Grignard Reagents
– Addition of a Grignard reagent to
formaldehyde followed by treatment with
H3O+ gives a 1° alcohol.

O
ether
CH3 CH2 -Mg Br + H- C-H
Formaldehyde
- +
O [ Mg Br] OH
HCl
CH3 CH2 -CH2 CH3 CH2 -CH2 + Mg2+
H2 O
A magnesium 1-Propanol
alkoxide (a 1° alcohol)
 Grignard Reagents
– Addition to any other RCHO gives a 2° alcohol.

Mg Br O
ether
+
H
Acetaldehyde
(an aldehyde)
- +
O [ Mg Br] OH
HCl + Mg2+
H2 O

A magnesium 1-Cyclohexylethanol
alkoxide (a 2° alcohol;
(racemic)
 Grignard Reagents
– Addition to a ketone gives a 3° alcohol.

O ether
Ph- Mg Br +

Phenyl- Acetone
magnesium (a ketone)
bromide
- + OH
O [ Mg Br] HCl + Mg2+
Ph H2 O Ph
A magnesium 2-Phenyl-2-propanol
alkoxide (a 3° alcohol)
 Grignard Reagents
Problem: 2-Phenyl-2-butanol can be
synthesized by three different combinations
of a Grignard reagent and a ketone. Show each
combination.

OH
C-CH2 CH3
CH3
 Organolithium Compounds
• Organolithium compounds are generally
more reactive in C=O addition reactions
than RMgX, and typically give higher
yields.
- +
O Li OH
O
Li
+ HCl
H2 O
Phenyl- 3,3-Dimethyl-2- A lithium alkoxide 3,3-Dimethyl-2-phenyl-
lithium butanone (racemic) 2-butanol
(racemic)
 Salts of Terminal Alkynes
• Addition of an alkyne anion followed by
treatment with H3O+ gives an -
acetylenic alcohol.

O HC C O - N a + HC C OH
-
HC C: N a + + HCl
H2 O
Sodium Cyclohexanone A sodium 1-Ethynyl-
acetylide alkoxide cyclohexanol
 Hydration of Terminal Alkynes

O
HO CCH3
H2 O 
H2 SO4 , Hg SO4
HO C CH
An -hydroxyketone
O

HO CH2 CH
1 . (s ia) 2 BH

2 . H2 O2 , NaOH
A -hydroxyaldehyde
 Addition of HCN
• HCN adds to the C=O group of an aldehyde or
ketone to give a cyanohydrin.
• Cyanohydrin: A molecule containing an -OH
group and a -CN group bonded to the same
carbon.

O OH
CH3 CH + HC N CH 3 C-C N
H
2-Hydroxypropanenitrile
(Acetaldehyde cyanohydrin)
 Addition of HCN
• Mechanism of cyanohydrin formation
– Step 1: Nucleophilic addition of cyanide
-
H3 C - H3 C O
C O + C N C
•
H3 C • H3 C C N
- Step 2: Proton transfer gives the
cyanohydrin and regenerates cyanide ion
nucleophile.
H3 C O
- H3 C O-H -
C + H C N C + C N

•
•
H3 C C N H3 C C N
 Cyanohydrins
• Acid-catalyzed dehydration gives an alkene.
OH acid
catalyst
CH3 CHC N CH2 = CHC N + H2 O
2-Hydroxypropanenitrile Propenenitrile
(Acetaldehyde cyanohydrin) (Acrylonitrile)

• Catalytic reduction of the cyano group gives a 1° amine.

OH OH
Ni
CHC N + 2 H2 CHCH2 NH2

Benzaldehyde 2-Amino-1-phenylethanol
cyanohydrin (racemic)
(racemic)
 Wittig Reaction

• The Wittig reaction is a very versatile

synthetic method for the synthesis of
alkenes from aldehydes and ketones.

+ -
O + Ph3 P-CH2 CH2 + Ph 3 P=O

Cyclohexanone A phosphonium Methylene- Triphenyl-

ylide cyclohexane phosphine oxide
 Phosphonium Ylides
Phosphonium ylides are formed in two steps:
• Step 1: Nucleophilic displacement of iodine by
triphenylphosphine.
SN 2 +
Ph 3 P + CH3 -I Ph3 P-CH3 I
Triphenylphosphine Methyltriphenylphosphonium iodide
(an alkyltriphenylphosphine salt)
• Step 2: Treatment of the phosphonium salt with
a very strong base, such as BuLi, NaH, or NaNH2
+
+
CH3 CH2 CH2 CH2 Li + H- CH2 -PPh 3 I
Butyllithium
+
CH3 CH2 CH2 CH3 + CH2 -PPh 3 + LiI
Butane A phosphonium
ylide
 Wittig Reaction
• Phosphonium ylides react with aldehydes and
ketones to give alkenes.
– Step 1: Nucleophilic addition of the ylide to
the electrophilic carbonyl carbon.
O CR2 -
:O CR2 O CR2
+ - +
Ph3 P CH2 Ph3 P CH2 Ph 3 P CH2
A betaine An oxaphosphetane
- Step 2: Decomposition of the oxaphosphatane.
O CR2
Ph 3 P= O + R2 C= CH2
Ph 3 P CH2
Triphenylphosphine An alkene
oxide
 Wittig Reaction
Examples:
O + Ph3 P + Ph 3 P=O

Acetone 2-Methyl-2-heptene

O
Ph + Ph + Ph 3 P= O
H + Ph 3 P Ph
Phenyl- (Z)-1-Phenyl-2- (E)-1-Phenyl-2-
acetaldehyde butene butene
(87%) (13%)

O O O
Ph Ph 3 P Ph + Ph 3 P= O
H + OEt OEt
Phenyl- Ethyl (E)-4-phenyl-2-butenoate
acetaldehyde (only the E isomer is formed)
 Wittig Reaction
– Some Wittig reactions are Z selective, others
are E selective.
– Wittig reagents with an anion-stabilizing
group, such as a carbonyl group, adjacent to
the negative charge are generally E selective.
O O
Ph3 P Ph 3 P
OEt OEt
Resonance contributing structures for an
ylide stabilized by an adjacent carbonyl group

– Wittig reagents without an anion-stabilizing

group are generally Z selective.
 Wittig Reaction
• Horner-Emmons-Wadsworth modification
– Uses a phosphonoester.

O
Br-CH2 -C-OEt O O
an -bromoester
( Me O) 2 P-CH2 -C-OEt + Me Br
An -phosphonoester
( Me O) 3 P O
Br-CH2 -C-R O O
Trimethyl-
an -bromoketone
phosphite (Me O) 2 P-CH2 -C-R + Me Br
An -phosphonoketone
 Wittig Reaction
– Phosphonoesters are prepared by
successive SN2 reactions.

O SN 2
( Me O) 3 P + CH2 -C-OEt
Br

OMe O O O
SN 2
CH3 -O-P-CH2 -C-OEt ( Me O) 2 P-CH2 -C-OEt + Me Br
OMe An -phosphonoester
Br
 Wittig Reaction
– Treatment of a phosphonoester with a strong
base followed by an aldehyde or ketone gives
an alkene.
– A particular value of using a phosphonoester-
stabilized anion is that they are almost
exclusively E selective.

1. strong O
O O O
base
( Me O) 2 P-CH2 -C-OEt OEt + Me O-P-O-
O
2. OMe
H Only the E isomer Dimethylphosphate
is formed anion
 Addition of H2O
• Addition of water (hydration) to the carbonyl
group of an aldehyde or ketone gives a geminal
diol, commonly referred to a gem-diol.
– A gem-diol is also referred to as a hydrate.

acid or
base OH
C O + H2 O C
OH
Carbonyl group A hydrate
of an aldehyde (a gem-diol)
or ketone
 Addition of H2O
– When formaldehyde is dissolved in water at 20°C,
the carbonyl group is more than 99% hydrated.
H H
OH
O + H2 O
OH
H H
Formaldehyde Formaldehyde hydrate
(>99%)
– The equilibrium concentration of a hydrated
ketone is considerably smaller.
OH
O + H2 O
OH
Acetone 2,2-Propanediol
(99.9%) (0.1%)
 Addition of Alcohols
• Addition of one molecule of alcohol to the
C=O group of an aldehyde or ketone gives
a hemiacetal.
• Hemiacetal: A molecule containing an -OH
and an -OR or -OAr bonded to the same
carbon.
acid or
base OH
O + H-OEt
OEt
A hemiacetal
 Addition of Alcohols
– Hemiacetals are only minor components of an
equilibrium mixture, except where a five- or
six-membered ring can form.
O
4
1 H 4 1
OH +
4 1
OH
OH O O
(S)-4-Hydroxypentanal Cyclic hemiacetals
(major forms present at equilibrium)

6 CH2 OH 6 CH2 OH
OH OH O
HO HO anomeric
HO 6 4 2 4 5 O 4 5 O carbon
5 3 1 H 3 2 1 + 3 2 1
OH OH HO OH HO OH
OH OH
D-Glucose  Anomer of D -glucose  Anomer of
(open chain form) cyclic hemiacetal D -glucose cyclic
(predominates hemiacetal
at equilibrium)
 Addition of Alcohols
– At equilibrium, the b anomer of glucose
predominates because the -OH group on the
anomeric carbon is equatorial.
6 CH OH OH
2 redraw as anomeric
6
HO anomeric a chair 4 carbon
5 O 5 O
conformation HOHO
4 carbon
3 2 1
OH (equatorial)
HO OH 3
2 1
OH OH
 Anomer

6 CH OH
2 redraw as OH
6 anomeric
HO anomeric a chair 4 carbon
4 5 O
5 O
carbon conformation HO
3 2 1 HO
HO OH 3
2 1

OH HO
OH(axial)
 Anomer
 Addition of Alcohols
• Formation of a hemiacetal is base catalyzed
– Step 1: Proton transfer from HOR gives an
alkoxide.
fast and
reversible
B - + H OR B H + - OR

– Step 2: Attack of RO- on the carbonyl carbon.

–
O O:
–
CH3 -C-CH3 + :O-R CH3 -C-CH3
OR
 Addition of Alcohols
– Step 3: Proton transfer from the alcohol to
O- gives the hemiacetal and generates a new
base catalyst.

– OH
O:
-
CH3 -C-CH3 + H OR CH3 -C-CH3 + OR
OR OR
 Addition of Alcohols
• Formation of a hemiacetal is also acid catalyzed.
Step 1: Proton transfer to the carbonyl oxygen.
+ H
O fast and O
reversible -
CH3 -C-CH3 + H-A CH3 -C-CH3 + A

Step 2: Attack of ROH on the carbonyl carbon.

+ H
O O-H
CH3 -C-CH3 + H-O-R CH3 -C-CH3
O+
H R
 Addition of Alcohols

Step 3: Proton transfer from the oxonium ion to

A- gives the hemiacetal and generates a
new acid catalyst.

OH OH
CH3 -C-CH3 CH3 -C-CH3 + H-A
+ OR
O
A
- H R
 Addition of Alcohols
• Hemiacetals react with alcohols to
form acetals.
Acetal: A molecule containing two -OR or
-OAr groups bonded to the same carbon.

+
OH H OEt
+ H-OEt + H2 O
OEt OEt
A hemiacetal A diethyl acetal
 Addition of Alcohols
Step 1: Proton transfer from HA gives
oxonium ion. H + H
HO O
-
R-C-OCH3 + H A R-C-OCH3 + A:
H H
An oxonium ion

Step 2: Loss of water gives resonance-

stabilized cation.
+
H H
O + +
R-C OCH3 R-C OCH3 R-C OCH3 + H2 O
H H H
A resonance-stabilized cation
 Addition of Alcohols
Step 3: Reaction of the cation with methanol gives
the conjugate acid of the acetal.
H + CH3
+ O
CH3 -OH + R-C OCH3 R-C OCH3
H H
A protonated acetal
Step 4: Proton transfer to A- gives the acetal and
generates a replacement acid catalyst.
H + CH3 OCH3
O
- (4)
A: + R-C OCH3 R-C-OCH3 + H-A
H H
An acetal
 Addition of Alcohols

– With ethylene glycol and other glycols, the

product is a five-membered cyclic acetal.

+ O
HO H
O + OH + H2 O
O
Cyclic acetal
Dean-Stark Trap
 Acetals as Protecting Groups

• Suppose you want to run the Grignard

reaction between these compounds.

O OH O
O
H Br ?? H
+ H

Benzaldehyde 4-Bromobutanal 5-Hydroxy-5-phenylpentanal

(racemic)
 Acetals as Protecting Groups
• The Grignard reagent prepared from 4-
bromobutanal will self-destruct! To avoid this:
– First protect the -CHO group as an acetal.
O + O
H + H2 O
Br OH Br
H + HO O
A cyclic acetal

– Then do the Grignard reaction.

- +
O Mg Br O
O
1 . Mg , e t h e r O
Br
O
2 . C6 H5 CHO
A chiral magnesium alkoxide
(produced as a racemic mixture)

– Hydrolysis (not shown) gives the target molecule.

 Acetals as Protecting Groups
• Tetrahydropyranyl (THP) protecting group.
THP group
H+
RCH2 OH +
O RCH2 O O
Dihydropyran A tetrahydropyranyl
ether

– The THP group is an acetal and,

therefore, stable to neutral and basic
solutions, and to most oxidizing and
reducing agents.
– It is removed by acid-catalyzed
hydrolysis.
 Addition of Nitrogen Nucleophiles
• Ammonia, 1° aliphatic amines, and 1° aromatic
amines react with the C=O group of aldehydes
and ketones to give imines (Schiff bases).

O +
H
CH3 CH + H2 N CH3 CH=N + H2 O

Acetaldehyde Aniline An imine

(a Schiff base)

+
H
O + N H3 N H + H2 O
Cyclohexanone Ammonia An imine
(a Schiff base)
 Addition of Nitrogen Nucleophiles
• Formation of an imine occurs in two steps:
Step 1: Carbonyl addition followed by proton
transfer.
O:- H H
O O
+
C + H2 N-R C N-R C N-R
H H
Step 2: Loss of H2O and proton transfer
+
H H H H
H O O +
+ C N-R + H O + H2 O
O H + C N-R C N-R
H H H An imine H
H O
H
 Addition of Nitrogen Nucleophiles
• A value of imines is that the carbon-nitrogen
double bond can be reduced to a carbon-
nitrogen single bond.

H+
O + H2 N - H2 O
Cyclohexanone Cyclohexylamine

H
H2 / N i
N N

(An imine) Dicyclohexylamine

 Addition of Nitrogen Nucleophiles

• Rhodopsin (visual purple) is the imine

formed in the eye between 11-cis-retinal
(vitamin A aldehyde) and the protein opsin.

11
12
+ H2 N-ops in

Rhodopsin
O N-o ps in
11-cis-Retinal H (Visual purple) H
 Addition of Nitrogen Nucleophiles
• Secondary amines react with the C=O group of
aldehydes and ketones to form enamines.
+
H
O + H-N N + H2 O

Cyclohexanone Piperidine An enamine

(a secondary amine)

– The mechanism of enamine formation involves

formation of a tetrahedral carbonyl addition
compound followed by its acid-catalyzed dehydration.
 Addition of Nitrogen Nucleophiles
• The carbonyl groups of aldehydes and ketones
react with hydrazine in a manner similar to their
reactions with 1° amines.
O + H2 NNH2 NNH2 + H2 O
Hydrazine A hydrazone
Reagent, H2N-R Name of Reagent Name of Derivative Formed
H2 N-OH Hydroxylamine Oxime

H2 N-NH Phenylhydrazine Phenylhydrazone

H2 N-NH NO2 2,4-Dinitrophenyl- 2,4-Dinitrophenylhydrazone

hydrazine
O2 N
O
H2 N-NHCNH2 Semicarbazide Semicarbazone
 Acidity of -Hydrogens

• Hydrogens alpha to a
T ype of Bond pK a
carbonyl group are more
acidic than hydrogens of CH3 CH2 O-H 16
alkanes, alkenes, and O
alkynes but less acidic CH3 CCH2 -H 20
than the hydroxyl
CH3 C C-H 25
hydrogen of alcohols.
CH2 = CH-H 44
CH3 CH2 -H 51
 Acidity of -Hydrogens
 -Hydrogens are more acidic because
the enolate anion is stabilized by:
1. Delocalization of its negative charge.
2. The electron-withdrawing inductive effect
of the adjacent electronegative oxygen.

-
O O O
-
CH3 -C-CH2 - H + :A CH3 -C CH2 CH3 -C=CH2 + H-A
Resonance-stabilized enolate anion
 Keto-Enol Tautomerism
• Protonation of the enolate anion on oxygen gives
the enol form; protonation on carbon gives the keto
form.

O O-
-
CH3 - C-CH2 CH3 - C= CH2
Enolate anion
H- A H- A
O OH
- -
A + CH3 - C-CH3 CH3 - C= CH2 + A
Keto form Enol form
 Keto-Enol Tautomerism
– Acid-catalyzed equilibration of keto and enol tautomers
occurs in two steps.
Step 1: Proton transfer to the carbonyl oxygen.

+ H
O fast and O
•
•

reversible -
CH3 -C-CH3 + H-A CH3 -C-CH3 + A
Keto form The conjugate acid
of the ketone
+ H
O OH
slow
StepCH
2:3 Proton transfer
-C-CH2 -H + :A to the base
-
CHA3 --C=
. CH2 + H-A
Enol form
 Keto-Enol Tautomerism
% Enol at
• Keto-enol Keto form Enol form Equilibrium
equilibria for
O OH
simple CH3 CH CH2 = CH 6 x 10-5
aldehydes and O OH
ketones lie far CH3 CCH3 CH3 C= CH2 6 x 10-7
toward the keto O OH
form. 1 x 10-6
O OH
4 x 10-5
 Keto-Enol Tautomerism
• For some molecules, the enol is the major form
present at equilibrium:
– For -diketones, the enol is stabilized by conjugation of
the pi system of the carbon-carbon double bond and the
carbonyl group.
– For acyclic -diketones, the enol is further stabilized by
hydrogen bonding.