PREPARATION OF

CARBONYL COMPOUNDS

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REVIEWS
SO FAR WE HAVE LEARNED SEVERAL METHODS
Ozonolysis of alkenes / alkynes
Periodate oxidation of vicinal diols
Oxidation of side chain of alkyl substituted arenes
Oxymercuration of alkynes
Hydroboration of alkynes
Now we will lean:
Oxidation of alcohols
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Oxidation of Alcohols

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OXIDATION OF ALCOHOLS
A dehydrogenation (loss of hydrogen = loss of 2H+
+ 2e-) is a form of oxidation!
carbon
- 2H

OXIDATION

H
hydrogen

REDUCTION

+ 2H

LOSS OF TWO
HYDROGENS
one from -H

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OXIDATION OF ALCOHOLS
The alcohol must have hydrogen(s)

1 alcohol

2 alcohol

no reaction
3 alcohol
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COMMON OXIDANTS
Mild

Mild

N+
H

Mild:

Cr2O722

PCC

PDC

Pyridinium
Chlorochromate

Pyridinium
Dichromate

1 OH to aldehyde
In anhydrous
Aldehyde to carboxylic acid
solvents
2 OH to ketone

Strong:

1 OH to carboxylic acid
2 OH to ketone

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In aqueous
solvents

Strong

K2Cr2O7
/H2SO4
Chromic Acid
(JONES REAGENT)

Strong

KMnO4
Permanganate
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CHROMIC ACID
EQUILIBRIA

JONES REAGENT
(A solution of CrO3 in dilute H2SO4)
H2 SO4
CrO3 + H2 O

H2 SO4
H2 CrO4

H2 Cr2 O7 + H2 O
x2

O
H O Cr O H
O
Chromic acid

H O Cr O Cr O H
O

Dichromic acid

Named after Prof. Sir Ewart Jones

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MECHANISM
O
HO Cr OH

Alcohols react with chromic

acid to form chromate esters.

..
R C O
.. Cr

H2O H2SO4

..
O
..

Chromate ester

HO Cr O :
+
H
H
O
..
R C O:
H
H
Primary alcohol
has two -H
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..+

..
R C O Cr O H
..
H H

..
H2O
..

MECHANISM

( continued )

..
H
: Cr O
..

aldehyde

..
..
R C O Cr O H
..
..
H

..

R C O:

..

H O:
H

H
Loss of two
electrons

H O:
+
H

The two lost

electrons
end up here.

Loss of
-hydrogen
FIRST OXIDATION

Oxidation
continues
(next slide)

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MECHANISM

( continued )

Requires
water and acid

hydrate
(an alcohol !)

R C O

R C O
H 2O

O
H

Oxidation continues because

the aldehyde forms a hydrate.
The hydrate is an alcohol (diol)
that has an -hydrogen.
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Oxidation
continues
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MECHANISM
O

O H
H

R C O Cr O H

H
H

R C O

:..O

HO Cr O
H

( continued )

H+

OH

O
Loss of -hydrogen,
loss of 2 electrons.

hydrate

Carboxylic
acid

R C O:

..

OH

..
O H
: Cr ..
O

SECOND OXIDATION

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.. H
H O+
H

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OXIDATION OF ALCOHOLS
Example: benzaldehyde from benzoic acid

1. LiAlH4
2. H2O

COH

CH

PDC
CH2Cl2

CH2OH
(81%)

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(83%)

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OXIDATION OF ALDEHYDES
The Tollens Test
metallic
silver

aldehyde

Ketones do
not react.

silver mirror

Remember that aldehydes

are easily oxidized.
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Quiz 15.1 Fill in the blanks

O
CH3CH2

O
CH3CH2C(CH2)3 CH3

1. CH3(CH2)3MgBr
2. H3O+

H2CrO4

(57%)

OH
CH3CH2CH(CH2)3CH3

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OXIDATION OF KETONES
- Ketones are much harder to be oxidized.
- Requires much harsh conditions, such as the use of
strong oxidant, heat
- In general, not a useful reaction except a few cases:
KMnO4/ H+

O
C

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CH3

O
C

H2CrO4 /

OH

H+

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Interconversion Of
Carboxylic Acids And
Derivatives

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16

REACTIONS OF CARBOXYLIC ACIDS

Most stuff you already knew!

We will learn a few more, before that, lets review some reaction patterns
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REVIEW: GENERAL MECHANISM

When a LG group is present, the carboxylic derivatives undergo

reaction via the addition / elimination.
Nu:- is usually O- or N- based.
There could be several proton transfer steps involved during the
process depending on reactants and conditions.

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REVIEW: GENERAL MECHANISM

When a LG group is present, the carboxylic derivatives undergo

reaction via the addition / elimination.
Nu:- is usually O- or N- based.
There could be several proton transfer steps involved during the
process depending on reactants and conditions.

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19

ACID HALIDE, ACID ANHYDRIDE,

ESTER, AMIDES FROM
CARBOXYLIC ACID

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Carboxylic Acids to Acid Halides

Carboxylic acids can be converted to the most reactive
acid chlorides with thionyl chloride

O
(CH3)2CHCOH

SOCl2
heat

O
(CH3)2CHCCl + SO2 + HCl
(90%)

The reaction works with or without a base.

- A clean reaction
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Carboxylic Acids to Acid Halides

Mechanism

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Carboxylic Acids to Acid Anhydrides

Carboxylic acids can react with an acyl chloride to
form an acid anhydride which is almost as reactive
as acyl halide. A base such as pyridine, Et3N etc is
required.
Example

CH3(CH2)5CCl +

CH3(CH2)5COH
pyridine

O O
CH3(CH2)5COC(CH2)5CH3 (78-83%)
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Quiz 16.2: Propose a reaction mechanism for the

following transformation

Quiz 16.3: Design a synthesis route for the following

two compounds from n-butane as the only carboncontaining compound.

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Carboxylic Acids to Esters

Fisher Esterification
Carboxylic acid and alcohol can undergo a condensation
under the catalysis of a strong acid to form an ester, this
process is called Fischer esterification and is reversible.

O
R'COH

H+
ROH

O
R'COR +

H2O

To drive the reaction going forward, either the formed

products such as H2O is removed or one of the starting
material is used in excess
- Base will not catalyze this reaction
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Carboxylic Acids to Esters

Mechanism for Fisher Esterification

Proton transfer

Only catalytic amount of acid is required

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Carboxylic Acids to Esters

Example for Fisher Esterification
O
COH + CH3OH
1 mol

6 mol
H2SO4

O
COCH3 +

H2O

70% yield based on benzoic acid

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Other Ways to Make Esters

From acid halide and alcohol

Quiz 16.4 Show the mechanism of above reaction

Refer to slide 22

From acid anhydride and alcohol

Using symmetric
anhydride
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Quiz 16.5 Show the mechanism of above reaction

Refer to slide 22
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Other Ways to Make Esters

The reaction to form ester between anhydride and alcohol
can also be catalyzed by strong acid

Quiz 16.6 Show the mechanism of above reaction

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Other Ways to Make Esters

Example:
O O
CH3COCCH3
Anhydride

CH3CHCH2CH3

H2SO4

OH

O
CH3COCHCH2CH3

(60%)

CH3

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Other Ways to Make Esters

Acyl chlorides react with alcohols to give esters
O

O
C6H5CCl + (CH3)3COH

pyridine

C6H5COC(CH3)3
(80%)

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Intramolecular Ester Formation

Lactonization
If in a compound, both a hydroxyl group and a
carboxylic acid function are found, it is possible to form
a cyclic ester (lactone) via an intramolecular
esterification also called lactonization
The process is especially favorable if 5- or 6-membered
is formed

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Intramolecular Ester Formation

Lactonization
O
HOCH2CH2CH2COH
4-hydroxybutanoic acid

H2SO4

O
O
4-butanolide

H2O

IUPAC nomenclature: replace the -oic acid ending of

the carboxylic acid by olide

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Transesterification
Convert One Ester to Another

Reversible, usually R3OH is used as a solvent

Example:
O

O
CH2OH

CH2OCR
NaOMe

RCOCH

HOMe

CH2OCR
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HOCH

RCOMe

CH2OH

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Carboxylic Acids to Amides

Amines do NOT react with carboxylic acids to give
amides - proton-transfer (acid-base) is the first step
The resulting ammonium carboxylate salts can be
converted to amides by heating to loose one H2O
O

O
RCOH

R'NH2

RCO

Dehydration

+
R'NH3
heat

O
not very common in laboratory
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RCNHR'

H2O
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Common Ways to Make Amides

From acid anhydride and amine

Mechanism

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Common Ways to Make Amides

From acid halide and amine

Quiz 16.7 Show the mechanism of above reaction

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Common Ways to Make Amides

Example

(87-91%)

(98%)
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Another Ways to Make Amides

Aminolysis of esters
Since RO- are better leaving group than -NH2, esters
can be readily converted to amides. No base is
required

Quiz 16.8 Show the mechanism of above reaction

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Another Way to Make Amides

Aminolysis of esters
Example:

O
H2C

CCOCH3 +
CH3

NH3

H2O
O

H2C

CCNH2

CH3OH

CH3
(75%)
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CARBOXYLIC ACIDS FROM

OTHER CARBOXYLIC
DERIVATIVES

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SYNTHESIS OF CARBOXYLIC ACIDS

Reviews

Most stuff you already knew!

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Acid Halides/Anhydrides to Carboxylic Acids

Acid halides readily react with water to give carboxylic
acids
O
O
C6H5CH2CCl

+ H2O

C6H5CH2COH + HCl

Acid anhydrides also readily react with water to give

carboxylic acids

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Esters to Carboxylic Acids

Esters are usually stable under neutral conditions, but
they can be hydrolyzed to gave carboxylic acids under
both acidic and basic conditions
Mechanism:
Both processes follow similar mechanism
1). nucleophillic addition (form the tetrahedral
intermediate)
2). Elimination of the alcohol portion of the original
ester to restore the carbonyl group

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Esters to Carboxylic Acids

Acid-catalysed hydrolysis of ester is just the reverse of
Fisher Esterification, which is a reversible processes.
Carboxylic acids are obtained directly.
O

O
+

RCOR'

H2O

H+

RCOH + R'OH

Use large excess of H2O to

push reaction to the right

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Esters to Carboxylic Acids

The base-catalysed hydrolysis of ester is an irreversible
process which gives carboxylate anion This process is
called saponification. Only after a protonation, the
carboxylic acid is obtained.
O

O
RCOR'

NaOH

RCO- Na+

+ R'OH

H3O+
Require stoichiometric
amount of base

O
RCOH

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SAPONIFICATION

Basic hydrolysis of the

glyceryl triesters (from
fats and oils) gives
salts of long-chain
carboxylic acids.
These salts are soaps

NaOH
heat

R = long aliphatic chain

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HOW TO DISSOLVE GREASE IN WATER

Grease particle

O H

Dirt trapped inside

O H
H

O H
H O

O H

H O

O H

H
H O

O H

H
H O
H

H O

O H

O H
H O
H

H
O H
H

O H
H

O H
H O H
H

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MICELLE
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Esters to Carboxylic Acids

Example

O
+

CHCOCH2CH3

H2O

Cl
HCl, heat
O
CHCOH

CH3CH2OH

Cl
(80-82%)
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Esters to Carboxylic Acids

Example
O
CH2OCCH3
CH3

NaOH

water-methanol, heat
O

CH2OH
CH3
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CH3CONa
(95-97%)
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Amides to Carboxylic Acids

Like esters, amides can be hydrolysed to carboxylic
acid irreversibly both in acidic and basic conditions.
Due to the poor leaving ability of R2N:- group, amides are
much harder to be hydrolysed than esters.
Acid catalyzed hydrolysis provides an ammonium salt
Base catalyzed hydrolysis provides the amine and
carboxylate

O
RCNHR' + H2O

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H+
HO-

+
RCOH + R'NH3
O
RCO -

+ R'NH2
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Amides to Carboxylic Acids

Example: Basic Hydrolysis
O
CH3CNH

O
KOH
H2O
heat

Br

NH2

CH3COK

Br
(95%)

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Amides to Carboxylic Acids

Example: Acid Hydrolysis
O
CH3CH2CHCNH2

O
H2O

CH3CH2CHCOH

H2SO4
heat

+
+ NH4 HSO4

(88-90%)

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Nitriles to Carboxylic Acids

Hydrolysis of nitriles resembles the hydrolysis of
amides - the reaction is irreversible
Ammonia is produced and is protonated to ammonium ion
in acid solution.
In basic media, carboxylate is produced.

O
H+
RC

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N + H2O

HO-

+
+
NH
RCOH
4
O
RCO -

+ NH3
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Nitriles to Carboxylic Acids

Example: Acid Catalysed Hydrolysis

O
CH2Br

NO2

CH2CN

CH2COH

NaCN

H2O

DMSO

H2SO4
heat
NO2

NO2
(92-95%)

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Nitriles to Carboxylic Acids

Example: Base Catalysed Hydrolysis
CH3(CH2)8CH2Cl

KCN
ethanolwater

CH3(CH2)8CH2C

(95%)
1. KOH, H2O,
heat
2. H3O+

O
CH3(CH2)9COH
(80%)
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Nitriles to Carboxylic Acids

Quiz 16.9 Show the mechanism of the below reaction

Hint: the reaction will proceed via an amide intermediate

Quiz 16.10 Show the mechanism of the below reaction

Hint: the reaction will proceed via an amide intermediate as well

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Quiz 16.11 Choose the correct product formed

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Quiz 16.12 Choose the correct statement

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Quiz 16.13: Ibuprofen is used primarily for treating fever, pain, and
inflammatory diseases such as rheumatoid arthritis. It is an
important ingredient in Motrin, Nurofen, Advil, and Nuprin. Apply
what you have learnt so far in Chem353, and design a synthesis
for Ibuprofen. You are only allowed to use ethanol and benzene as
the carbon sources for your project.

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