Hudan Taufiq

Farmasi FK Unissula

 Memahami Struktur & Sifat senyawa karbonil

Memahami Definisi & penggolongan senyawa karbonil
Memahami Reaksi umum senyawa karbonil: Adisi
nukleofilik; Subtitusi asil nukleofilik; Subtitusi alfa (yang
meliputi: Keto-enol tautomerisme, reaktivitas enol,
halogenasi alfa dari keton & aldehid; Keasaman hidrogen alfa
: pembentukan enolat, reaktivitas enolat, sintesis ester
malonat, sintesis ester asetoasetat); Kondensasi karbonil:
Mekanisme umum; Kondensasi aldehid & keton; Reaksi aldol :
dehidrasi produk aldol, reaksi aldol campuran; Kondensasi
Claisen, Siklisasi Dieckman, reaksi Michael, reaksi enamina
Stork, reaksi Annelasi Robinson

 Fessenden, R.J. dan Fessenden J.S., 1997, Kimia

Organik, Edisi kedua, Alih bahasa A.H. Pudjaatmaka,
Erlangga, Surabaya.
Masterton W.L. and Hurley C.N., 2009, Chemistry:
Principle and Reaction , 6 th edition, Brooks/Cole
cengage Leroring.
McMurry. 2008. Organic Chemistry. Thomson
Brooks/Cole. Australia.
Mc Murry J., 2004, Organic Chemistry, Wards-worth Inc.,
California.
Salomons, T.W.G, 1997, Fundamentals of Organic
Chemistry, John Willey & Sons, New York.

The carbonyl group (>C=O) is the functional

group found in compounds such as aldehydes,
ketones, and carboxylic acids.

In aldehydes the carbonyl group is at the end of the

carbon chain and so has at least one hydrogen
attached to it.

In ketones the carbonyl group is in the middle of a

carbon chain and so has two alkyl groups attached
to it.

Although double bonds require more energy to break than single bonds,
compounds with double bonds tend to be more reactive as addition reactions
are possible.
Some of the chemical properties of aldehydes and
ketones result from the polar nature of the C=O
bond.

The positive charge on the carbon atom makes it open to attack by

nucleophiles.

Aldehydes and ketones can be reduced, forming primary and secondary

alcohols respectively.

Aldehydes may also be oxidized to carboxylic acids.

R
Carbonyl

Aldehyde

R'
Ketone

OH

Carboxylic
Acid

Carboxylate
Ester

O
120o
R

OR'

Planar, sp2 Hybridized Carbon

Carbonyl Features 1 s and 1 p Bond
Carbonyl Group Quite Polarized (Cd+, Od-)

Resonance Structure for Carbonyl Reflecting Bond Polarization??

Nucleophilic Addition to Carbonyl Groups:

Nu

Nucleophile

Nu

d
O

Carbonyl

Addition Product:
TETRAHEDRAL

Oxidation of Alcohols/Reduction of Carbonyls:

O
More
Hydrogen
Content

Oxidation
R

OH
Primary
Alcohol

Reduction R
H
Aldehyde

Less
Hydrogen
Content

Categories of Carbonyl Compounds

Carbonyl
Compounds
may be
grouped into
two broad
categories
based upon
whether or
not they take
part in
Nucleophilic
Substitution
Reactions

Aldehydes and Ketones

O
C
R
R

XX

Aldehydes and Ketones - X = H and R

respectively ; these carbonyl compounds do
not undergo nucleophilic substitution
reactions. That is to say, the H and R groups
are never substituted by other groups. Both Hand R- make poor leaving groups.

Carboxylic Acids and their Derivatives

O
C
R

Carboxylic acids and their derivatives

X = some heteroatom (O, Cl, or N).
Nucleophilic substitution reactions are
possible for these carbonyl compounds
because the electronegative heteroatom can
stabilize a negative charge and form good
Leaving Groups.

Polarity of the Carbonyl

Groups
The carbon-oxygen double bond of the
carbonyl group is extremely polarized in the
direction of the highly electronegative oxygen.
This polarization is responsible for the
characteristic reactions of carbonyl compounds
d- :O:

nucleophilic oxygen reacts with

acid and other electrophiles

d+ C
electrophilic carbon reacts with
bases and other nucleophiles

General Reactions Of
Carbonyl Compounds
Nucleophilic Addition Reactions
Nucleophilic Acyl Substitution

Nucleophilic Addition Reactions

Chapter 09
There are two different ways in which a nucleophile can add
to a carbonyl compound. Each way leads to a different
nucleophilic addition reaction but the mechanisms for both
reactions involves the same 1st step.
In this step, the nucleophile bonds to the carbonyl carbon
and thereby causes a carbon-oxygen bond to break. The
carbonyl carbon rehybridizes from sp2 to sp3 and the
carbonyl oxygen becomes negatively charged. At this point
the tetrahedral intermediate can either be protonated to form
an alcohol (NaBH4, LiAlH4, or Grignard Reduction) or a
non-bonded e- pair on the nucleophile can be used to form a
second bond to the carbonyl carbon. The new bond
formation causes expulsion of the carbonyl oxygen as H2O.

First Type of Nucleophilic

Addition
Alcohol Formation
Ketones and
Aldehydes react with
NaBH4, LiAlH4, and
Grignard reagents to
form alcohols

Second Type of Nucleophilic Addition

Imine formation Ketones and
Aldehydes react
with 1o amines to
form imines .

Nucleophilic Acyl Substitution

Theses reactions do not apply to aldehydes
and ketones. These reactions involve the
substitution of the nucleophile for the X
residue of the carbonyl compound.

O
C

Nu

O
C

+
Nu

X-

Nucleophilic Acyl Substitution

CARBONYL CONDENSATION
REACTIONS

CARBONYL CONDENSATION
REACTIONS

Aldol Reaction
Dehydration of Aldol Products
Intramolecular Aldol Reaction
Claisen Condensation Reaction
Intramolecular Claisen
Condensation
Michael Reaction
Stork Enamine Reaction
Robinson Annulation Reaction

General Mechanism of Carbonyl

Condensation
O
C
R

H
OH
C
One carbonyl partner
with an alpha hydrogen
atom is converted by base
into its enolate ion.

OH2

Nucleophilic
Donor

C
R

C:

:O:
C

This enolate ion acts as a

nucleophilic donor and
adds to the electrophilic
carbonyl group of the
acceptor partner

..

C
R

Electrophilic
Acceptor

O
..

OH2

O
C
R

C
C

OH

New C-C Bond

Protonation of the tetrahedral alkoxide ion

intermediate gives the neutral condensation
product.

-OH

ALDOL REACTION
occurs between two aldehyde or ketone
molecules with a catalytic base
reaction can occur between two components
that have alpha hydrogens
reversible condensation reaction
two highlights: enolate formation and
nucleophilic attack at a carbonyl carbon
Aldol products are: alpha--unsaturated
aldehydes/ketones and -hydroxy
aldehydes/ketones

Mechanism of the Aldol Reaction

HO:
Base removes an
acidic alpha hydrogen
from one aldehyde
molecule, yielding
a resonancestabilized enolate ion.

O
H

C
H

: O:

C
CH3

+ H2O

.. C
H

H H

..
:O : -

O
CH3 C C C
H HH H H

The enolate ion attacks

a second aldehyde
molecule in a
nucleophilic addition
reaction to give a
tetrahedral alkoxide ion
intermediate.

H 2O

:OH

C
+
OH
C
C H3
HH H H
C

Protonation of the alkoxide ion intermediate yields

neutral aldol product and regenerates the base
catalyst.

Dehydration of Aldol Products:

Synthesis of Enones
-hydroxy aldehydes and -hydroxy ketones
formed in aldol reactions can be easily dehydrated
to yield conjugated enones
Dehydration is catalyzed by both acid and base
Reaction conditions for dehydration are only
slightly more severe than for condensation
Conjugated enones are more stable than
nonconjugated enones

Dehydration of Aldol Products

Base-catalyzed

OH
OH

.. :O :

OH

C
C

C
H

Enolate ion

O
C

C
C

OH-

Acid-catalyzed

OH

O
C

OH2+
C

H
Enol

O
C

H3O

Mixed Aldol Reaction

If two similar aldehydes/ketones react under
aldol conditions, 4 products may be formed
A single product can be formed from two
different components :
If one carbonyl component has no alphahydrogens or if one carbonyl compound is much
more acidic than the other.

Intramolecular Aldol Reaction:

Treatment of certain dicarbonyl compounds
with base can lead to cyclic products
A mixture of cyclic products may result ,
but the more strain-free ring is usually
formed

Intramolecular Aldol Reaction of 2, 5hexanedione yields 3-methyl-2cyclopentenone

O
C CH3
H b a
C
CH3
H C C
H H O

2,5- Hexanedione

Path A

-OH

O H
C C- H
H
C
CH3
C C
H
H H
O
O H
C C H
H
C
CH3
C C
H
H
H
OH

NaOH, H2O

..
:O
H
..
O H
H C C H
H C
CH3
C
C
H
H
OH

O H O
+ 2

CH
3
3-Methyl-2-cyclopentenone

Path b
NaOH, H2O

O
C CH3
H
C
CH3
C C
H
H H O
-OH

..

O H
H
C C H
H
C
CH3
H C C
H
O

..

O H
H
C C H
H
C
CH3
H C C
H
O

..
:O
H
..

OH
H3 C

H3C

H
CH3

H3 C
+
H 2O

(2-Methylcyclopropenyl)ethanone
(NOT formed)

Claisen Condensation Reaction

Carbonyl condesation that occurs between two
ester components and gives a -keto ester product
Reaction is reversible and has a mechanism similar
to aldol reaction
Major difference from aldol condensation is the
expulsion of an alkoxide ion from the tetrahedral
intermediate of the initial Claisen adduct
1 equivalent of base is needed to drive the reaction
to completion because the product is often acidic

Mechanism of Claisen Condensation:

involves nucleophilic acyl substitution of an ester
enolate ion on the carbonyl group of a second
ester molecule
tetrahedral intermediate expels an alkoxide leaving
group to yield an acyl substitution product

Mechanism of the Claisen

Condensation Reaction

O
Ethoxide base abstracts an
acidic alpha hydrogen
atom from an ester
molecule, yielding an ester
enolate ion

CH3COEt
- OEt

O
:CH2COEt

EtOH

Nucleophilic donor

:O:
CH3C OEt

..
:O: -

In a nucleophilic addition,
this ion adds to a second
ester molecule, giving a
tetrahedral intermediate.

Electrophilic
acceptor

CH3C CH2COEt
OEt

The tetrahedral intermediate

is not stable. It expels ethoxide
ion to yield the new carbonyl
compound, ethyl acetoacetate.

But ethoxide ion is basic enough

to convert the beta-keto ester
product into its enolate, thus
shifitng the equilibrium and driving
the reaction to completion.

O
O
CH3CCH2COEt + EtO-

O_ O
CH3CCHCOEt + EtOH
..

H3O+
Protonation by addition of acid
in a separate step yields the final
product.

O
CH3CCH2COEt + OH2

Mixed Claisen Condesation

occurs only when one of the two ester
components has no alpha-hydrogens, and
thus cant form enolate ion
can also be carried out between esters and
ketones resulting a synthesis of -diketones

Example of Mixed Claisen

Condensation
O
C OEt
Ethyl Benzoate

O
1. NaH/THF

C H3 COEt
Ethyl Acetate
(Donor)

(Acceptor)

Ethyl benzoylacetate

C CH2 COEt
EtO H

2. H30 +

Intramolecular Claisen Condensation:

Dieckmann Cyclization
can be carried out with diesters
works best on 1, 6-diesters and 1,7-diesters
5-membered cyclic -ketoesters result from
Dieckmann cyclization of 1,6-diesters
6-membered cyclic -keto esters result from
cyclization of 1,7-diesters

Examples of Intramolecular
Claisen Condensation
O

O
OEt

1. Na+ -OEt, ethanol

O
Diethyl hexanedioate
(a 1,6 -Diester)

O
C

OEt
EtOH

2. H3O+

Ethyl 2-oxocyclopentanecarboxylate
(82%)

OEt

O
1. Na+ -OEt, ethanol

OEt
O

O
C

2. H3O+

OEt

+
OEt
Diethyl heptanediote
(a 1,7- Diester)

Ethyl-2-oxocyclohexane carboxylate

Intramolecular Claisen Condensation

Mechanism
O
OEt
Base abstracts an acidic
alpha-proton from the
carbon atom next to one
of the ester groups,
yielding an enolote ion.

H
H

COOEt

Na + - OEt

..
:

tEO

EtOH

COOEt
Intramolecular nucleophilic addition of the ester enolate
ion to the carbonyl group of the second ester group at the
other end of the chain then gives a cyclic tetrahedral
intermediate.

tEO

H
COOEt

:
O
.
.

Loss of alkoxide ion from the tetrahedral

intermediate forms a cyclic beta-keto ester.

. .

+
Deprotonation of the
acidic beta-keto ester
gives an enolate
ion

H
COOEt

tEO
.

COOEt
O

EtOH

H 3O +

which is protonated
by addition of
aqueous acid at the
endoth the reaction to
generate the neutral
beta-keto ester
product.

+H

O
2

H
COOEt
O

Michael Reaction
Conjugate addition of a carbon nucleophile to an

alpha, -unsaturated acceptor

Best Michael Reactions:
Between unusually acidic donors (-ketoesters or diketones)
Unhindered alpha,-unsaturated acceptors

Stable enolates are Michael donors, and alpha,unsaturated compounds are Michael acceptors

The Michael Reaction

O
C
The base catalyst
removes an acidic alpha
proton from the starting
beta-keto ester to
generate a stabilized
enolate ion nucleophile.

EtO

O
C
CH3

C
H

H
+

Na - OEt

O O
C - C
The nucleophile adds
to the alpha,beta-keto
EtO ..C CH3
unsaturated ketone
H
O
H
electrophile in a
Michael reaction to
C
C
generate a new enolate
H
H
C
C
3
as product.
O

C ..
H3C C
H

+ EtOH

H HO
C C
C

CH3

H
CO2Et

The enolate product

abstracts an acidic
proton, either from
solvent or from starting
keto ester, to yield the
final addition product.

EtOH

O H H O
C C C
H3C C C CH3 + EtOH H
H
CO2Et

Some Michael Acceptors and

Michael Donors
Michael Acceptors
H2C CHCHO Propenol
H2C CHCO2Et Ethyl Propanoate
H2C CHC N Propenenitrile
H2C CHCOCH3 3-Buten-2-one
H2C CHNO2 Nitroethylene
H2C CHCONH2 Propenamide

Michael Donors
Beta-Diketone
RCOCH2COR'
RCOCH2CO2Et Beta-Keto Ester
EtO2 CCH2 CO2Et Malonic Ester
RCOCH2C N Beta-Keto nitrile
RCH2NO2
Nitro compound

Stork Enamine Reaction

enamine adds to an alpha,-unsaturated carbonyl

acceptor in a Michael- type process

Overall reaction is a three-step sequence:
Step 1: Enamine formation from a ketone
Step 2: Michael-type addition to an alpha, unsaturated carbonyl compound
Step 3: Enamine Hydrolysis back to ketone
net effect of Stork Enamine reaction sequence is
the Michael addition of a ketone to an alpha,unsaturated carbonyl compound

Example of Stork Enamine Reaction

O
N

N ..

H2C

-H2O
Cyclohexanone
O
N+
..
CH2CHCCH3

CHCCH3

An enamine

OH2

O
CH2CH2CCH3

CH2CH2CCH3

N
H

A 1,5-diketone

Robinson Annulation Reaction: Carbonyl

Condensation Reaction in Synthesis
leads to the formation of substituted cyclohexenones
2 step process:
Michael reaction
Intramolecular Aldol reaction
Treatment of a -diketone or -keto ester with an alpha, unsaturated ketone leads first to a Michael addition, which
is followed by intramolecular aldol cyclization