02536595d9d9d-Aldehydes and Ketones

A LDEHYDES AND K ETONES
Aldehydes and ketones are similar in structure in that both classes of compounds possess a
C O bond, called a carbonyl group.
O O
R H R R
aldehyde ketone
The carbonyl group of an aldehyde is flanked by a hydrogen atom, while the carbonyl group
of a ketone is flanked by two carbon atoms.
SYNTHESIS OF ALDEHYDES AND KETONES

I. From alkanes
O2
R CH3 R CHO
Mo2O3
II. From alkenes

a) Alkenes can be converted into aldehydes or ketones by reductive ozonolysis.
i) O3
R CH CH R 2RCHO
ii) Zn /H2O
or Zn / AcOH
or DMS
or Ph3P
R R O
O3
R C C R 2R C R
ketone
b) Alkenes can be converted to aldehydes or ketones on dihydroxylation followed by

oxidative cleavage.
R' H O
i) OsO4 or cold.alk.KMnO4
R C C R R C R' + R CHO
ii) HIO4 or Pb  OAc 4
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2 ALDEHYDES AND KETONES
c) Oxo process
lkenes can be hydroformylated by treatment with carbon monoxide and hydrogen
Alkenes
over a catalyst. The most common catalysts are cobalt carbonyls and rhodium
complexes. Cobalt catalysts are less active than the rhodium
um type. Commercially, this
is called the oxo process.
chain terminal alkenes > straight-chain

The order of reactivity is straight-chain straight internal
alkenes >branched-chain
chain alkenes.
O
Co2  CO 8
R CH CH2 + CO + H2 R CH2 CH2 C H
or Co  CO 4 H
high pressure
d) Wacker’s process
The industrial oxidation of ethylene to acetaldehyde under an atmosphere of oxygen
using PdCl2 and CuCl2 as catalysts is known as the Wacker-Smidt
Wacker process.
H O
CuCl2 / HCl
H2C CH2 + PdCl2 + H2O
H + Pd 0  + 2HCl
O2
ethylene H H
acetaldehyde
Terminal alkenes react much faster than internal or 1,1-disubstituted

1,1 disubstituted alkenes and they are
almost exclusively converted to the corresponding methyl ketones.
ketones
PdCl2
H H O
H2O
CuCl2 R CH3
R H
O2
terminal alkene methyl ketone
III. From alkynes

a) Catalytic hydration
OH O
dil.H2SO4
R C CH R C CH2 R C CH3
HgSO4
ALDEHYDES AND KETONES 3
b) Hydroboration-oxidation
oxidation
O
i) Sia 2BH
R C CH R CH CH OH R CH2 C H
ii) H2O2 , OH
H R O
i) Sia 2BH
R C C R R C C OH R CH2 C R
ii) H2O2 , OH
c) Reductive ozonolysis
O O
Reductive ozonolysis
R C C R R C C R
O O
Reductive ozonolysis
R C CH R C C H
d) Oxidation with cold.alk. KMnO4

O O
cold.alk.KMnO4
R C C R R C C R
e) Oxidation with SeO2
O O
SeO2
R C CH R C C H
O O
SeO2
R C C R R C C R
IV. From alkyl halides

O
DMSO
R CH2 X R C H
X O
DMSO
R CH R R C R
X O
aq.NaOH
R C R R C R
X
V. From alcohols: Primary and secondary alcohols can be converted to aldehydes and ketones
respectively with mild oxidizing agents. Mild oxidizing agents are
(i) Sarett and Collins reagent
(ii) Pyridinium chlorochromate (PCC) (or) Corey
Corey-Suggs
Suggs reagent
(iii) Pyridinium Dichromate (PDC)
(iv) Manganese dioxide (for allylic or benzylic alcohols)
(v) Copper metal
(vi) Ceric ammonium nitrate (CAN)
(vii) Halogens
(viii) Swern oxidation [DMSO & (COCl)2]
(ix) Silver carbonate (Ag2CO3) (Reactivity: Allylic > 20 > 10)
(x) Oppenauer oxidation [Al-isopropoxide]
(xi) Fenton’s Reagent
VI. From carboxylic acids
Aldehydes can be synthesized

d
a) By heating a mixture of the calcium salts of formic acid and any one of its homologues.
O O
R C O H C O O

Ca + Ca 2R C H + 2CaCO3
R C O H C O
O O
b) By passing a mixture of the vapours of formic acid and any one of its homologues over
manganous oxide as catalyst at 300 C .
MnO
RCO2H + HCO2H RCHO + CO2 + H2O
R2CO is obtained as by product. The reaction proceeds via the manganous salt.
Ketones can be synthesized

a) By heating the calcium salt of any monocarboxylic acid other than formic acid.
O
R C O O

Ca R C R + CaCO3
R C O
O
If a mixture of calcium salts is used, mixed ketones are obtained.
R1CO2 2 Ca + R2CO2 2 Ca 2R1COR 2 + 2CaCO3
b) By passing the vapour of any monocarboxylic acid other than formic acid over
manganous oxide at 300 C .
MnO
2RCO2H R 2CO + CO2 + H2O
Decarboxylation of acids
a) Ketonic decarboxylation
The reaction has been performed on dicarboxylic acids, where upon cyclic ketones are
obtained.
COOH
ThO2
(CH 2 ) n  CH2 n C O

COOH
This process, called Ruzicka cyclization, is good for the preparation of rings of six and
seven members and, with lower yields, of C8 and C10 — C30 cyclic ketones.
b) Keto carboxylic acids undergo decarboxylation on heating.

β-Keto
O O O

H3C C CH H2 C OH H3C C CH3 + CO2
Mechanism
O
CH2 C CH2 CH3

R C O C C + O C O
R O R O
O H
H
c) Glycidic acids give aldehydes on decarboxylation.

H
R O
O O
H
O O C
R C R C R O
R R
O O O
OH
CO2
R H R H
R O R OH
Ex:
O O
COOH

1) CO2
O O
COOH

2) COOH
2CO2
Reaction with alkyl lithium

Ketones can often be obtained by treatment of the lithium salt of a carboxylic acid with an
alkyllithium reagent, followed by hydrolysis.
O O
i) R'Li  excess 
C C
R OH
ii) H3O R R'
The R' group may be aryl or primary, secondary, or tertiary alkyl and R may be alkyl or aryl.
The compounds MeLi and PhLi have been employed most often. Tertiary alcohols are side
products.
Mechanism
O O
R' Li
C C + R' H
R OH R OLi
O LiO OLi O
H3O
C + R' Li C C
R OLi R R' R R'
Ex:
O O
C C CH3
OH i) CH3CH2Li  excess  CH2
ii) H3O
VII. From acid chlorides

Reduction of acid halides
a) Rosenmund reduction
The Rosenmund reduction is a hydrogenation process in which an acyl chloride is
selectively reduced to an aldehyde.
The reaction is catalysed by palladium on barium sulfate,, poisoned with quinolone.

In the absence of poisoned
poison catalyst,, the resulting aldehyde can be further reduced to
alcohol.
O O
H2 , Pd
C C
R Cl BaSO4 R H
quinoline
Mechanism
O O O
Pd  0  H Pd H
Cl H
R Cl oxidative R Pd ligand R Pd
addition exchange
reductive elimination
O
+ Pd  0 
R H
b) Acyl halides can also be reduced to aldehydes by treatment with DIBAL-H

DIBAL and tributyl
tinhydride.
O O
DIBAL-H
C C
R Cl 78 º C R H
O O
Bu3SnH
C C
R Cl R H
Reaction with organometallic

rganometallic reagents
When the organometallic compound is a Grignard reagent or organolithium
compounds, ketones are generally not obtained because the initially formed ketone
reacts with a second molecule of RMgX to give the salt of a tertiary alcohol.
alcohol Ketones
have been prepared in this manner by the use of low temperatures, inverse addition
(i.e., addition of the Grignard reagent to the acyl halide rather than the other way),
low.
excess acyl halide, and so on, but the yields are usually low.
O O
'
R—MgX (1mole)
C C (not best method)
R Cl  or  R—Li
' (1 mole) R R'
Acyl halides react cleanly and under mild conditions with lithium dialkylcopper
reagents to give high yields of ketones. Another type of organometallic reagent that
gives good yields of ketones when treated with acyl halides are organocadmium
reagents R2Cd .
O O
R'2CuLi
C C (Better method)
R Cl  or  R'2Cd R R'
Me Me Me Me
MeO Cl Me2CuLi MeO Me
O O O O
Identify the products in the following series of reactions.
O
C
Cl LiAlH  t  BuO 3 NaBH4 Conc.H2SO4
? ? ?
78 º C EtOH
Sol:
O
C CHO
Cl LiAlH  t  BuO3 NaBH4 OH
78 º C EtOH
Conc.H2SO4
Identify the products in the following reactions.

O O
C
Cl i) H2C CH 2 CuLi Cl i)  H2C CH 2 Cd
a) ? b) ?
ii) H2 /Ni ii) Al  Oi Pr 3
CH3CH  OH  CH3
__________________________________________________________________________________________________
VIII. From esters
Reduction of esters
O O
DIBAL-H
R C OR R C H
78 º C
IX. From nitriles

Reduction of nitriles
a) Stephen reduction
The preparation of aldehydes by the reduction of nitriles with the combination of
stannous halide/HCl in an organic solvent is known as the Stephen aldehyde
synthesis or Stephen reduction.
reduction
i) SnCl2 / HCl
R C N R C O
ii) H2O / 
H
Mechanism
H H H
2 H HCl Cl
R C N R C N H R C N H
H2O
H
O
R
Ex
CN CHO
i) SnCl2 / HCl
ii) H2O / 
OMe OMe
b) Nitriles can also be reduced to aldehydes upon treatment with DIBAL-H at lower
temperature followed by hydrolysis.
i) DIBAL-H O
78 º C
R C N R C H
ii) H3O
Reaction with Grignard reagent

Ketones can be prepared by addition of Grignard reagents to nitriles and subsequent
hydrolysis.
R ' MgX H3O

R C N R C NMgX R C O
R' R'
With HCN acid base reaction takes place,, so aldehydes cannot be synthesized by this reaction.
i) PhMgBr Ph
CN
ii) H3O
O
Give the products of following reaction.

reaction
CH3
NBS NaCN i) SnCl2 / HCl

? ? ?
DMF ii) H3O
Sol:
O
Br C C
CH3 H2 C H 2C N H2 C H
NBS NaCN i) SnCl2 /HCl

/ HCl
DMF ii) H3O

reaction
C
H2 C N
i) CH3CH2MgBr DIBAL-H conc.H2SO4

? ? ?
ii) H3O
Sol:
O OH
O
C C CH
C
H2C N H 2C CH2 H2C CH2
CH3 CH3
i) CH3CH2MgBr DIBAL-H
ii) H3O
conc.H2SO4
CH
C
HC CH2
CH3

reaction
C N
i) PhCH2MgBr NaBH4 Conc.H2SO4
? ? ?
EtOH
ii) H3O
__________________________________________________________________________________________________
Preparation of aromatic aldehydes and ketones

CH3 H 2C Br CHO
NBS  CH2 6 N4
Cl
CH3 HC CHO
Cl
Cl2 / h aq.NaOH
(Benzylidene
chloride)
CH3 CHO
O2 /MnO
500 °C
Etard reaction
The Etard reaction is a chemical reaction that involves the direct oxidation of an aromatic or
heterocyclic methyl group to an aldehyde using chromyl chloride.
O
CrO2Cl2 H
Mechanism
O COCH 3
CH 3 HC CHO
O COCH 3
CrO3 H3O
Ac2O
In the absence of acetic anhydride the oxidation leads the formation of carboxylic acid.
CH 3 COOH
i) CrO3
ii) H3O
PHYSICAL PROPERTIES
dipole dipole attractions between the molecules of
Polarization of the carbonyl group creates dipole-dipole
ketones and aldehydes, resulting in higher boiling points than for hydrocarbons and ethers
of similar molecular weights. Ketones and aldehydes have no O—H
H bonds, however, so their
molecules cannot form hydrogen bonds with each other. Their boiling points are therefore
lower than those of alcohols of similar molecular
molec weight. The following compounds of
molecular weight 58
8 or 60 are ranked in order ofincreasing boiling points. The ketone and
the aldehyde are more polar and higher-boiling
higher than the ether and the alkane, but lower
lower-
boiling than the hydrogen--bonded alcohol.
O
CH3CH2CH2CH3 H3C O CH 2CH3 H 3CH2 C C H
butane methoxyethane propanal
b.p. 0 °C b.p. 8 °C b.p. 49 °C
O
H 3C C CH3 H3CH2CH2 C OH
acetone i-propanol
b.p. 56 °C b.p. 97 °C
Although pure ketones and aldehydes cannot engage in hydrogen bonding with each other,
they have lone pairs of electrons and can act as hydrogen bond acceptors with other
H bonds. For example, the —OH hydrogen of water or an alcohol can
compounds having O—H
form a hydrogen bond with the unshared electrons on a carbonyl oxygen atom.
 
 O   O 
H H H R
O O
 C  C
R R' R H'
Because of this hydrogen bonding, ketones and aldehydes

aldehydes are good solvents for polar
hydroxylic substances such as alcohols. They are also remarkably soluble in water.
Acetaldehyde
cetaldehyde and acetone are miscible (soluble in all proportions) with water. Other ketones
and aldehydes with up to four carbon atoms are fairly soluble in water. These solubility
properties are similar to those of ethers and alcohols, which also engage in hydrogen bonding
with water.
Formaldehyde and acetaldehyde are the most common aldehydes. Formaldehyde is a gas at
room temperature, so it is often stored and used as a 40% aqueous solution called formalin.
When dry formaldehyde is needed, it can be generated by heating one of its solid derivatives,
usually trioxane or paraformaldehyde. Trioxane is a cyclic trimer, containing three
dehyde units. Paraformaldehyde is a linear polymer containing many formaldehyde
formaldehyde
units.
Physical properties of some representative ketones and aldehydes

Melting Boiling H2O
IUPAC Density
Common name Structure point point Solubility
name (g/cm3)
(°C) (°C) (%)
ketones
2-propanone Acetone CH3COCH3 –95 56 0.79 
Methyl ethyl
2-butanone CH3COCH2CH3 –86 80 0.81 25.6
ketone (MEK)
Methyl n-propyl
propyl CH3COCH2CH2CH3
2-pentanone –78 102 0.81 5.5
ketone
3- pentanone Diethyl ketone CH3CH2COCH2CH3 –41 101 0.81 4.8
2-hexanone CH3CO  CH2 3 CH3 –57 127 0.83 1.6

Aldehydes
Methanal Formaldehyde HCHO or CH2O –95 –21 0.82 55
Ethanal Acetaldehyde CH3 CHO –123 21 0.78 
Propanal Propionaldehyde CH3CH2CHO –81 49 0.81 20
Butanal n-butyraldehyde
butyraldehyde CH3  CH2 2 CHO –97 75 0.82 7.1
2-methylpropanal Isobutyraldehyde  CH3 2 CHCHO –66 61 0.79 11
CHEMICAL PROPERTIES
Introduction to nucleophilic addition reactions
The electrophilicity of a carbonyl group derives from resonance effects as well as inductive
effects.

O O O
C C C

Resonance Induction
One of the resonance structures exhibits a positive charge on the carbon atom, indicating
that the carbon atom is deficient in electron density     . Inductive effects also render the
carbon atom deficient in electron density. As a result, this carbon atom is particularly
electrophilic and is susceptible to attack by a nucleophile. Molecular orbital calculations
suggest that nucleophilic attack occurs at an angle of approximately 107 to the plane of the
hybridization state of the carbon atom changes.
carbonyl group, and in the process, the hybridization
sp2 sp3
(Trigonal planar) (Tetrahedral)
The carbon atom is originally sp2 hybridized with a trigonal planar geometry. After the
attack, the carbon atom is sp3 hybridized with a tetrahedral geometry.
In general, aldehydes are more reactive than ketones toward nucleophilic attack. This
observation can be explained in terms of both steric and electronic effects.
a) Steric effects
A ketone has two alkyl grou ps (one on either side of the carbonyl) that contribute to
groups
steric hindrance in the transition state of a nucleophilic attack. In contrast, an
aldehyde has only one alkyl group, so the transition state is less crowded and lower in
energy.
b) Electronic effects
A ketone has two electron-donating
electron alkyl groups that can stabilize the + on the
carbon atom of the carbonyl group.
electron donating group.

In contrast, aldehydes have only one electron-donating group
O O
R  R R  H
a ketone an aldehyde
has two electron-donating
donating alkyl groups has only one electron-donating
donating alkyl group
that stabilize zes the partial positive charge
ize the partial positive charge that stabilizes
The ++ charge of an aldehyde is less stabilized than a ketone. As a result, aldehydes are more
electrophilic than ketones and therefore more reactive.
In general, the reactivity order of aldehyde and ketones towards nucleophilic addition is
O O O O
  
R H Ph H R R Ph Ph
des and ketones react with a wide variety of nucleophiles. Some nucleophiles require
Aldehydes
basic conditions, while others require acidic conditions.
Mechanism of nucleophilic addition under basic conditions
O O O OH
Nuc H H
Nuc Nuc
Aldehydes and ketones also react with a wide variety of other nucleophiles under
acidicconditions.
Mechanism of nucleophilic addition under acidic conditions

H
O O OH
H A Nuc
Nuc
In acidic conditions, the first step plays an important role. Specifically, protonating the
carbonyl group generates a very powerful electrophile.
H H
O O O
H A
Very powerful electrophile
It is true that the carbonyl group is already a fairly strong electrophile; however, a protonated
carbonyl group bears a full positive charge, rendering the carbon atom even more
electrophilic. This is especially important when weak nucleophiles, such as H2O or ROH, are
employed.
When a nucleophile attacks a carbonyl group under either acidic or basic conditions, the
position of equilibrium is highly dependent on the ability of the nucleophile to function as a
leaving group.
I. Oxygen nucleophiles
a) Hydrate Formation
When an aldehyde or ketone is treated with water, the carbonyl group can be
converted into a hydrate.
O HO OH
+ H2O
hydrate
The position of equilibrium generally favors the carbonyl group rather than the
hydrate, except in the case of very simple aldehydes, such as formaldehyde.
O HO OH
+ H2O
H 3C CH3 H3C CH3
99.9%
O
HO OH
+ H2O
H H H H
 99.9 %
The rate of reaction is relatively slow under neutral conditions but is readily enhanced
in the presence of either acid or base. That is, the reaction can be either acid catalyzed
c
or base catalyzed, allowing the equilibrium to be achieved much more rapidly.
Mechanism of base-catalyzed
catalyzed hydration
O O O OH
H
OH H H
H H H OH H OH
H H
Mechanism of acid-catalyzed
catalyzed hydration
H H H
H O H O O
O O OH OH
H H H
H
H H H H H O H OH
H H
H
The extent of hydration (in water) of a small selection of carbonyl compounds.
Name Structure Equilibrium Constant K
O
Acetone 0.001
O
Acetaldehyde 1.06
H
O
Formaldehyde 2280
H H
O
Cl
Chloral H 2000
Cl
Cl
Formaldehyde reacts with water so readily because its substituents are very small: a
steric effect. Electronic effects can also favour reaction with nucleophiles-
nucleophiles
electronegative atoms such as halogens attached to the carbon atoms next to the
carbonyl group can increase the extent of hydration according to the number of
electron withdrawing power. They increase the
halogen substituents and their electron-withdrawing
polarization of the carbonyl group, which already has a positively polarized carbonyl
carbon, and make it even more prone to attack by water. Trichloroacetaldehyde
(chloral, Cl3CHO )is hydrated completely in water, and the product ‘chloral hydrate’
can be isolated as crystals and is an anaesthetic.
Ex:
O HO OH
H2O
1)
Cyclopropanone on conversion to its hydrated form, gets relieved from angle

strain, so equilibrium is favorable towards hydrated form.
O O
H
H2O O
2) O
O
H
O O
ninhydrin
In aqueous solution of ninhydrin the equilibrium is more favorable towards
hydrated form due to existence of hydrogen bonding in the hydrated form.
For most ketones, hydrate formation is unfavorable, because the equilibrium favors the
ketone rather than
han the hydrate. However, the equilibrium for hydration of hexafluoroacetone
favors formation of the hydrate: Provide a plausible explanation for this observation.
O HO OH
+ H2O
F3C CF3 F3C CF3
 99.99%
b) Acetal formation
In acidic conditions, an aldehyde or ketone will react with two molecules of alcohol to
form an acetal, in
n the presence of acid catalyst. Common acids used for this purpose
toluenesulfonic acid (TsOH), sulfuric acid  H2SO4  and dry HCl.
include para-toluenesulfonic
O OR OR
H
+ 2ROH + H2O
acetal
Mechanism
H
H O
O O OH OH
H A R A
H
O OR
Hemiacetal
R
H A
H
H R O H H
OR O R O
A R O H2O
OR OR OR
acetal
For many simple aldehydes, the equilibrium favors formation of the acetal, so
aldehydes are readily converted into acetals by treatment with two equivalents of
alcohol in acidic conditions.
O EtO OEt
H
+ 2EtOH + H2O
H H H H
However, for most ketones, the equilibrium favors reactants rather than products.
O EtO OEt
H
+ 2EtOH + H2O
H3 C CH3 H3 C CH3
By removing water as it is formed, the reaction can be forced to completion.

Cyclic acetals are more resistant to hydrolysis than their acyclic counterparts. They
make they form quite readily, even from ketones. For the formation
are also easier to make—they
of an acyclic acetal, three molecules go in and two come out, but for a cyclic acetal,
ace
two molecules go in and two molecules come out, so S is negative for acyclic acetals,
whereas S less negative for cyclic acetals.
acyclic acetal formation

O RO OR
2ROH + + H2O
R R
3 molecules in 2 molecules out
cyclic acetal formation

O
HO OH + O O + H2O
R R
2 molecules in 2 molecules out
Ex:
O
O O
H
1) + HO OH
H2O
O O O
O O
OR H OR
2) + HO OH
H2O
HO OH O O
O H2SO4
3)
H2O
O TsOH EtO OEt

excess EtOH
4)
H2O
Note
Acetals can be hydrolysed in aqueous acid but are stable to base.
Draw a plausible mechanism for the following transformation
O EtO OEt
H2SO4 
excess EtOH
H2O
Sol: Step-1
H H
H H H
O O O Et OEt
H O O HO O HO
Et Et Et
Hemiacetal
Step-2
H Et H
H H H
OEt H O O O Et OEt
HO OEt O EtO O EtO
H O
Et H2O Et Et
Acetal
Draw a plausible mechanism for each of the following transformations.

O MeO OMe O H2SO4 , EtO OEt
H2SO4 ,
excess EtOH
a) excess MeOH b) H2O
H2O
O MeO OMe
TsOH,
excess MeOH
c)
H2O
Predict the product of each of the following reactions.
O O
H2SO4 , HO OH
excess MeOH H2SO4
a) ? b) ?
H2O H2O
Predict the product(s) for each reaction below
O O OMe
H3O OMe H3O
a) ? b) ?
O O H3O O H3O
c) ? d) ?
__________________________________________________________________________________________________
c) Hemiacetals
In most of the cases, it is very difficult to isolate the intermediate hemiacetal.
O RO OH RO OR
+ 2ROH + ROH + H2O
Hemiacetal Acetal
For ketones the equilibrium generally favors the reactants unless water is removed,
which enables formation of the acetal. The hemiacetal is not favored under either set
of conditions (with or without removal of water). However, when a compound contains
both a carbonyl group and a hydroxyl group, the resulting cyclic hemiacetal is stable
and can often be isolated.
OH
O O
H
HO
Cyclic hemiacetal
Although the cyclic hemiacetal (also called ‘lactol’) product is more stable, it is still in
equilibrium with some of the open-chain
open chain hydroxyaldehyde form. Its stability, and how
fiv and six-membered
easily it forms, depend on the size of the ring: five- six rings are free
from strain (their bonds are free to adopt 109 or 120 angles—compare
angles the three-
six membered hemiacetals are common. Among the most
membered rings), and five or six-membered
important examples are many sugars.
Ex:
HO HO
OH O
1) HO O HO
HO HO OH
OH OH
Glucose (> 99%)
OH
H O
O OH
HO
2) HO
HO OH HO OHH
Ribose cyclic ribose
O O
O OH O
Ph Ph
3) P P
Ph Ph
O
O
OH
Note
Hemiacetal formation is catalysed by acid or base, but acetal formation is possible
only with an acid catalyst because an OH group must be made into a good leaving
group.
Draw a plausible mechanism for the following transformation

O
HO O
OH H2SO4
Compound A has molecular formula C8H14O2 . Upon treatment with catalytic acid,
compound A is converted into the cyclic hemiacetal. Identify the structure of compound A.
HO
O
H
Compound A
II. Nitrogen nucleophiles

a) In mildly acidic conditions, an aldehyde or ketone will react with a primary amine to form
an imine.
CH3
O N
H H H
CH3NH2
Imines are also called Schiff bases, named after Hugo Schiff, a German chemist who
first described their formation.
Mechanism
H H
H N
O O OH OH
H A R A
H H
N N
H
R R
Carbinolamine
H A
H H
R H R O
N A N H2O
H
N
Imine
R
The pH of the solution is an important consideration during imine formation, with the
rate of reaction being greatest when the pH is around 4.5. If the pH is too high (i.e., if
no acid catalyst is used), the carbonyl group is not protonated and the carbinol
carbi amine
is also not protonated, so the reaction occurs more slowly.
If the pH is too low (too much acid is used), most of the amine molecules will be
protonated.
H
H O
H H
H
R N R N H
H H
A nucleophile not
a nucleophile
The rate of imine formation as a function of pH.

Like
ike acetals, imines are unstable with respect to their parent carbonyl compound and
amine, and must be formed by a method that allows removal of water from the
reaction mixture.
Me
O Me N Ph
H
+
Ph Me H2N Ph Ph Me
imine 72% yield
In general, they are stable enough to be isolated only if either the C or N of the imine
double bond bears an aromatic substituent. Imines formed from ammonia are
unstable, but can be detected in solution.
CHO
NH
+ NH3 + H2O
b) Stable products are formed with other nitrogen nucleophile like hydroxylamine,
phenyl hydrazine and semicarbazide and these products are generally white solids.
OH
O N
+ NH2OH
ketone hydroxylamine oxime
NHPh
O N
+ PhNHNH2
ketone phenylhydrazine phenylhydrazone
O NH
H2
O NH2
O NH
N
+ NH
H 2N
ketone
semicarbazide semicarbazone
2,4 DNP are yellow or orange crystalline solids, so

The hydrozones obtained from the 2,4-DNP
2,4-DNP
DNP is used to test presence of aldehydes and ketones.
NO2
O2 N
NO2
NH
O N
ketone O2 N
NH
H2N
2,4-dinotrophenyl
hydrazine (2,4-DNP)
(or) Brady's reagent
These compounds are more stable than imines because the electronegative
substituent can participate in delocalization of the imine double bond. Delocalization
decreases the small positive charge on the carbon atom of the imine double bond and
making it less susceptible to nucleophilic attack. Oximes, hydrazones, and
semicarbazones require acid or base catalysis to be hydrolysed.
OH OH
N N
HO
N O
H2SO4
Ph Ph
H2O
O O
 70% yield 
_______________________________________________________________________________________________
Predict the major product for each of the following reactions

reactions.
O
N 2
NH
H, NH3
a) ? b) O ?
H2O H,  H2O
Predict the major product for each of the following intramolecular reactions.
reactions
O O
a) H b) H
NH2 ? NH2 ?
H H2O H2O
Identify the reactants that you would use to make each of the following imines
imines.
N N N
a) b) c)
Predict the product of each of the following reactions.

reactions
O H
O H
HO NH
H2 H2 N NH2
a) ? b) ?
H2O H2O
Identify the reactants that you would use to make each of the following compounds.
compounds
N
OH
a) b) NH2
N
Beckmann rearrangement
When oximes are treated with PCl5 or a number of other reagents, they rearrange to
substituted amides in a reaction called the Beckmann rearrangement.
rearrangement
Among other reagents used have been concentrated H2SO4 , formic acid, liquid SO2 , SOCl2 ,
POCl3 and AlCl3 .
HO
N O
PCl5
C C R'
R R' R N
H
Mechanism
HO H2O
N N
H R'
C C C N R C N R'
R R' R R' R
H2O
O
R R' R R'
C R' C N C N
R N
HO H H2O
H
Of the groups attached to the carbon of the C N unit, the one that migrates in the
Beckman rearrangement is generally the one anti to the hydroxyl, and this is often used as a
method of determining the configuration of the oxime.
Ex:
OH OH2 OH2 H
N N
N N OH N O
H2SO4 H
1)
OH Ph
N HN
2) H
Ph Ph Ph O
TsO
N HN
Al2O3
3)
O
4) Aldoximes give cyanides as the exclusive product.

OH
N
H
R C N
R H
c) In acidic conditions, an aldehyde or ketone will react with a secondary amine to form an
enamine.
R R
O N
H
H
+ N
R R
an enamine
Enamines are ,  unsaturated amines.
Mechanism
H R
H N
O O OH OH
H A R A
H R
N N
R
R R
Carbinolamine
H A
H H
R R R R O
N A N H2O
R
H N
Enamine R
This mechanism of enamine formation is identical to the mechanism of imine
formation except for the last step.
R H R
O N N
H RNH2
RNH2
an imine
R R R R
O N N
H
H R 2NH
R2NH
an enamine
Note
Tertiary amines can only give salts of the following type.
HO NR 3 X
Stork enamine reaction

The synthesis of -alkyl- or acyl carbonyl compounds via the alkylation or acylation of the
corresponding enamines is known as the Stork enamine synthesis.
N N I CH3
CH3I H
excess MeOH CH3
reflux
2-methyl-
cyclohexanone
1-cyclohexyl-
pyroolidine
N N CN O NC
CN H
1-cyclopentenyl
pyrrolidine
3-(2-oxocyclopentyl)-
propionitrile
3 4
R R
N 3 4 3 4
R R R R
O N N
2
H
2 2
1 R R R
R solvent/catalyst 1 1
R R
aldehyde or ketone  HOH enamine
i) R 5 — X ii) H /H2O
O
2
1  R
R
5
R
-alkylated
-alkylated ketone
or aldehyde
Write the products in the following transformation.

O
O
H i) H3C C Cl
+ ? ?

N ii) H3O
III. Sulfur nucleophiles

a) In acidic conditions, an aldehyde or ketone will react with two equivalents of a thiol to
form a thioacetal.
O RS SR
H
+ 2RSH + H2O
Thioacetal
O
H
+ HS SH S S + H2O
Cyclic
thioacetal
When treated with Raney nickel, thioacetals undergo desulfurization, yielding an

alkane.
Raney Ni H H
S S
R R
R R
O H H
i) H, HS SH
ii) Raney Ni
Ex:
O
PhLi RX HgCl2
R C H +
1)
S S S S S S SH SH
H3O
R
 thio acetal 
Thioacetal can be hydrolyzed to aldehydes or ketones in presence of HgCl2 .
PhLi RX NaNH2
2)
S S S S S S S S
R
 thio acetal  R'X
O
HgCl2
R C R' +
SH SH S S
H3O
R R'
b) Bisulfite addition compounds

Bisulfite addition products are formed from aldehydes, methyl ketones, cyclic ketones
(generally seven-membered
membered and smaller rings) and a keto esters, upon treatment with
a-keto
sodium bisulfite. Most other ketones do not undergo the reaction, probably for steric
reasons. The reaction is reversible (by treatment of the addition product with either
acid or base) and is useful for the purification of the starting compounds, since the
addition products are soluble in water and many of the impurities are not.
O HO SO3Na
+ NaHSO3
R R' R R'
Mechanism
Sodium bisulfite
O O H O O
O OH
H O Na S Na S
S O O O OH
Na
O R R' R R' R R'
bisulfite addition
compound
After purification the bisulfite addition compound can be hydrolysed back to the
aldehyde in dilute aqueous acid or base.
stir together in
O HO SO3 Na
ice bath
+ NaHSO3
R H dilute acid R H
(or) base crystalline solid
IV. Carbon nucleophiles

a) Addition of organometallic
organome reagents
Aldehydes and ketones are converted into alcohols upon treatment with various
organometallic reagents followed by treatment with protic solvent.
O OH
i) MeLi, THF
R H ii) H2O Me H
R
O OH
i) PhLi, THF
R H ii) H2O Ph H
R
secondary alcohol
O OH
i) n-BuLi, THF
R R ii) H2O R
R
tertiary alcohol
O OH
i) PhMgBr, Et2O
R H ii) H2O Ph H
R
Predict the major product of each reaction below

below.
O O
i) EtMgBr H i) PhMgBr
a) ? b) ?
ii) H2O ii) H2O
Identify the reagents necessary to accomplish each of the transformations below.

below
O
OH Me OH O O
H i) PhMgBr
a) b) O ?
ii) H3O
__________________________________________________________________________________________________
b) Cyanohydrin formation
When treated with hydrogen cyanide (HCN), aldehydes and ketones are converted into
cyanohydrins, which are characterized by the presence of a cyano group and a
hydroxyl group connected to the same carbon atom.
O HO CN
HCN
a cyanohydrin
This reaction was found to occur more rapidly in mildly basic conditions. In the
presence of a catalyt
catalytic
ic amount of base, a small amount of hydrogen cyanide is
deprotonated to give cyanide ions, which catalyze the reaction.
Mechanism
O O OH
C N H C N
CN CN
In the first step, a cyanide ion attacks the carbonyl to produce a tetrahedral
intermediate. This intermediate then abstracts a proton from HCN, regenerating a
cyanide ion. In this way, cyanide functions as a catalyst for the addition of HCN to the
carbonyl group.
Rather than using a catalytic amount of base to form cyanide ions,

ions the reaction can
simply be performed in a mixture of HCN and cyanide ions (from KCN). The process is
reversible, and the yield of products is therefore determined by equilibrium
concentrations. For most aldehydes and unhindered ketones,
ketones the equilibrium favors
formation of the cyanohydrin.
O HO CN
KCN, HCN
H3C CH3 H3C CH3

 78 % 
O HO CN
H KCN, HCN H
 88 % 
HCN is a liquid at room temperature and is extremely hazardous to handle because it
is highly toxic and volatile (b.p. = 26 °C). To
To avoid the dangers associated with
handling HCN, cyanohydrins can also be prepared by treating a ketone or aldehyde
with potassium cyanide and an alternate source of protons, such as HCl.
O HO CN
KCN, HCl
O HO CN
i) NaHSO3
70% yield
Me Me ii) NaCN Me
Me
Mechanism
O O
O Na S OH HO CN
i) NaHSO3 O ii) NaCN
Me Me Me Me Me Me
+
NaSO3
O OH
OH O O
O S H
O O O CN
S O S
O CN O
Me Me Me Me
Me Me
Cyanohydrins are useful in syntheses, because the cyano group can be further treated
to yield a range of products.
N
HO C HO NH2
i) LAH
R H ii) H2O R H
N O
HO C HO C
H3O,  OH
R H R H
Ex:
1) Hydroxyacids by hydrolysis of CN in cyanohydrin.
O HO CN HO CO2 H
NaCN HCl
Ph Me HCl, Et2O Ph Me H2O Ph Me
2) Amino alcohols by reduction of CN in cyanohydrin.
O NH2
HO CN HO
NaHSO3 LiAlH4
H H H
NaCN, H2O
NC
O H HO H
NaCN
3)
OPh H OPh
O OH
NaCN, H2O
4) CN
N N
 95% yield 
Predict the major product for each reaction below.

O
i) KCN, HCN O
i) KCN, HCl
ii) LAH ?
a) ? b) H
iii) H2O ii) H3O, 

below
O
OH OH
OH OH
OH NH2
a) b)
__________________________________________________________________________________________________
c) Wittig reaction
Aldehyde or ketones on treatment with phosphorus ylides produce alkenes.
H Ph H H
O C
C P Ph
H Ph
Identify the reagents necessary to prepare each of the following compounds using a Wittig
reaction.
a) b) c)
d) e)

below
OH
a) b)
Reactions due to -hydrogen

hydrogen
a) Racemization
Racemization can be achieved by simply mixing equal quantities of two pure
enantiomers. Racemization can also occur in a chemical interconversion. For example,
when (R)-3-phenyl butanone
phenyl-2-butanone is dissolved in aqueous ethanol that
contains NaOH or HCl
HCl,, a racemate is formed. The racemization occurs by way of an
former stereocenter becomes planar and hence
intermediate enol form in which the former
achiral. An incoming group can approach from either side of the plane, so there is an
equal probability that protonation back to the chiral ketone will produce either an R or
an S form, resulting in a racemate.
Ph H Ph Ph H H Ph
H
+
or OH
O OH O O
R planar R S
achiral
recemic mixture
b) Deuterium exchange
Due to the acidic nature of -hydrogens
hydrogens they can be exchanged with deuterium by
reaction with D2O (heavy water). The process is accelerated by the addition of an acid
or base; an excess of D2O is required. The end result is the complete exchange of all
-hydrogens
hydrogens with deuterium.
O O
D2O
H D
D3O or OD
Mechanism
O O
OD
H + HOD
D
O
O D D O
D + D2O
Ex:
O O
D2O
CH3 CH3
H3 C D 3C CD 2
OD
c) Halogenation
Carbonyl compounds can be halogenated in the -position
position by halogens in acidic or
basic solutions. Ketones can usually be cleanly brominated using acetic acid as
solvent.
O O
Br2
Br
HOAc
acetone bromoacetone
Mechanism
H H
O O O
AcO H
H Br Br Br
enol
O
Br
Lewis acids make excellent catalysts for the bromination of ketones.

O O
Br2 ,
0.75 mol% AlCl3 , Et2O Br
100% yield 
Bromination occurs nowhere else in the molecule not on the benzene ring. This is
because only one position can form an enol and the enol is more reactive towards
bromine than the aromatic ring.
Mechanism
AlCl3 AlCl3 AlCl3 AlCl3
O O O
R R R
H Br Br
O
R
Br
In base, bromination is different and more complicated because it usually won’t stop
with the introduction of one halogen atom.
O O O
OH
H Br + Br
Br Br
rst step was the removal of a proton and the protons between the carbonyl group
The first
and the bromine atom in the product are more acidic than those in the original
electron withdrawing bromine atom. Bromoacetone forms an
acetone because of the electron-withdrawing
enolate faster than acetone does.
O O O
OH
H Br + Br
Br Br
Br Br Br
Dibromoacetone is formed. Now we have one remaining proton in between the
carbonyl group and two bromine atoms. It is even more acidic and so forms a new
enolate ion even more quickly. The first pr
product
oduct observable in any amount is
tribromoacetone.
O O O
OH
H Br Br + Br
Br Br Br
Br Br Br Br
tribromoacetone
Why does acid-catalysed

catalysed halogenation work better?
Acid-catalysed
catalysed halogenationcan
halogenation be made to stop after one halogen is introduced if
catalysed halogenation will continue if
only one equivalent of halogen is used. Acid-catalysed
there is more halogen available.
O O O
1  Br2 1  Br2
Br Br Br
HOAc HOAc
bromoacetone 1,3-di-bromoacetone
However, the second halogen goes on the other side of the carbonyl group, if it can. It
is evidently the case that thesecond halogenation
halogenation is slower than the first.
fi Most of the
intermediates are positively charged and hence destabilized bythe presence of a
halogen. The bromoketone is less basic than acetone so less of the reactive protonated
form is present.This slows down any further
further electrophilic attack.
Addition of a second bromine to the same position in acid solution (this does not usually
happen)
H H H
O O O O
Br Br Br Br
H H Br Br H H
OAc
The transition state for proton removal illustrates why bromine slows this step down.
The part of the structure close to the bromine atom is positively charged.
H #
O
Br
H H OAc
The halogenation of an unsymmetrical dialkyl ketone gives different results in acid

and in base. In base halogenation occurs preferentially on a methy
methyl group, that is, on
the less highly substituted side. In acid
acid solution by contrast, the first
fi (and only)
halogenation occurs on the more substituted side of the carbonyl group.
Halogenation in base
O O O
I2
I + CHI3
NaOH NaOH OH
I I
Halogenation in acid
O OH O
Br2 Br2
HOAc
Br
Ex:
O O O
Br
H3O Br
1) +
Br2
major minor
O O
Br
NaOH Br
2)
Br2
O O
i) NaOH, Br2
3) OH
ii) H3O
Predict the major product obtained when each of the following compounds is treated with
bromine  Br2  together with sodium hydroxide (NaOH) followed by aqueous acid  H3O  .
O
O O
a) b) c)
30. Identify the reagents that you would use to accomplish each of the following transformations
(you will need to use reactions from previous chapters).
OH O
a) OEt
COOH
b) O O
d) Alkylation of the -position

position
Alkylation via enolate ions
The -position
position of a ketone can be alkylated via a two-step
two step process: (1) formation of an
enolate followed by (2) treating the enolate with an alkyl halide.
O O
R
i) LDA
ii) RX
In this process, the enolate ion functions as a nucleophile and attacks the alkyl halide
in an SN 2 reaction.
O O
R
R X
With an unsymmetrical ketone, two possible enolates can be formed.
O O O
R R R
base base
Thermodynamic enolate Kinetic enolate

 more substituted   less substituted 
The more-substituted
substituted enolate is more stable and is called the thermodynamic enolate.
The less substituted enolate is less stable, but it is formed more rapidly and is
therefore called the kinetic enolate
enolate.
When the kinetic enolate is desired, LDA is used at low temperature ((−78°C). LDA is a
sterically hindered base and can more readily deprotonate the less hindered α
position, thereby forming the kinetic enolate. Low temperature is necessary to favor
formation of the kinetic enolate
late and to prevent equilibration of the enolates via proton
transfers. When the thermodynamic enolate is desired, a non-sterically
non hindered base
(such as NaH) is used, and the reaction is performed at room temperature. Under
these conditions, both enolates
enol are formed and an equilibration process occurs that
favors the more stable, thermodynamic enolate. In this way, alkylation can be
achieved at either α position by carefully choosing the reagents and conditions.
O O O
R R R R
i) LDA,  78 C i) NaH,  25 C
R
ii) RX ii) RX
For each of the following reactions, predict the major product and proposea mechanism for
its formation.
O
O
i) LDA i) NaH
a) ? b) ?
ii) CH3I
ii) CH2Br
i) LDA
O
ii) EtI
c) ?
i) LDA
ii) CH3I
__________________________________________________________________________________________________
e) Aldol condensation
An aldol condensation is a condensation reaction in organic chemistry in which an
enol or an enolate ion reacts with a carbonyl compound to form a -hydroxyaldehyde or
-hydroxyketone
hydroxyketone (an aldol reaction), followed by dehydration to give aconjugatedenone.
O O O R ''
H + + H2O
R R'' R''' R R '''
H
R' R'
Mechanism
O
enol mode H
O OH
O O O O H
catalytic H R' H2O
R CH3 R CH2 R R' R R'

H H
enol aldol condensation
aldol addition
product product
enolate mode O
O OM O OM
base
H R'
R CH3 H CH2 R R'
enolate H
Elimination of water from an alcohol in basic solution is difficult as hydroxide is a bad
leaving group. In the last step of aldol condensation, iitt is the carbonyl group that
allows elimination. These are E1cB reactions
reactions.
OH O
OH O O
H
H H H H
HO
Ex:
O OH OH
H H
1)
cyclopentanone enol
Mechanism
H H
O O O
H
O OH OH
H
The acid-catalysed
catalysed dehydration step (E1 elimination)
elimination)..
O O
O
OH OH2
H
H H
O
O OH O O O
O
2) H
t-Bu t-Bu t-Bu t-Bu
t-Bu
O
H H
O OH
t-Bu t-Bu
 60  70% yield 
O O
O base O O
3)
lactone
O O OH
NaOH
4)
Not isolated
Crossed aldol condensation

The aldol condensation between two different aldehydes or ketones is known as
crossed aldol condensation.
O O O O HO H O
+ +
H H H H H
+ NaOH
O O O O HO H O
H + H H+ H H
+ NaOH
O O O O HO H O
H + H H+ H H
+ NaOH
O O O O HO H O
H + H H + H H
+ NaOH
Ex:
O O O
H NaOH
1) +
H2O /EtOH
NO 2 NO 2
 99% yield 
O O Ph O
2) base
+
Ph Ph Me H Ph H
Note
For success of crossed aldol reactions
1) One partner only must be capable of enolization.
2) The other partner must be incapable of enolization and be more electrophilic
than the enolizable partner.
Intramolecular aldol reactions

Compounds that possess two carbonyl groups can undergo intramolecular aldol
reactions.
Consider the reaction that
t occurs when 2,5-hexanedione
hexanedione is heated in the presence of
aqueous sodium hydroxide.
O O
NaOH

O
Ex:
O
O
acid or base
1)
 nearly 100% yield 

O
O
O O
H
2)
Mechanism
OH O
O OH
O
eight-membered cyclic OH
transition state
OH O
O OH
O OH
six-membered cyclic
transition state
O
six-membered ring
product
85% yield
O
O
3) KOH
O one product formed in

90% yield
O O
KOH
4) CO 2H
CO 2 H
O
 97% yield 
O CH3
O
1 KOH
2
5) 5
8
O
Z-undeca-8-en,2,5-dione cis-jasmone, 80% yield
Write the product of the following transformation.

transformation
O CN
Et3N H3O
H 5 C6 C H + H2 C ? ?
 ,  CO2
COOEt

transformation
O CN
Et3N H3O
H 5 C6 C CH3 + H2C ? ?
 
CN

transformation
O
O C CH3
i) Et3N, 
H 5 C6 C H + H2 C ?
C CH3 ii) H3O , 
Draw the condensation product obtained when each of the following compounds is heated in
the presence of aqueous
s sodium hydroxide.
O
O
a) b) H c)
H
H
O
O O
d) e) O f)
Identify the starting aldehyde or ketone needed to make each of the following compounds via
an aldol condensation.
CHO
O H
a) b) c)
H O
butanone is heated in the presence of aqueous sodium hydroxide, two

When 2-butanone
constitutionally isomeric condensation products are obtained. Draw both products.
__________________________________________________________________________________________________
f) Cannizzaro reaction
When reacted with concentrated NaOH (50 wt%)
wt%) or other strong bases (e.g., alkoxides),
aliphatic and aromatic aldehydes with no   hydrogen undergo an intermolecular
hydride-transfer
transfer reaction known as the Cannizzaro reaction. This is a
disproportionation reaction, one molec ule of aldehyde oxidizes another to the
molecule
corresponding carboxylic acid and is reduced to the corresponding primary alcohol in
a maximum 50% yield. If the aldehyde has -hydrogens,
hydrogens, the aldol reaction will take
ternatively, high yields of alcohol can be
place faster than the Cannizzaro reaction. Alternatively,
obtained from almost any aldehyde when thereaction is performed in the presence of
an excess of formaldehyde. This process is called the crossed Cannizzaro reaction. -
annizzaro reaction.
Keto aldehydes undergo an intramolecular Cannizzaro
H
R H R H NaOH/H2O R H R ONa
+ +
O O OH O
R  alkyl  no   hydrogen  or aryl 1° Alcohol
Carboxylic
acid salt
Mechanism
OH H
OH H
O
O O
R H R H R
R H
RDS
O O O
O H O O R
H H
+ H O + O H
R O R R O H
When concentration of OH is low, the rate = k substrate OH .

2
When concentration of OH is high, the rate = k substrate  OH .

2 2
Ex:
CHO COOK CH2OH
KOH
1) +

O
2) OD
CH3OD + HCOO
H H 
Crossed Cannizzaro reaction

In crossed Cannizzaro reaction the more reactive aldehyde undergoes oxidation and
forms salt of carboxylate, whereas less reactive aldehyde undergoes reduction and
forms alcohol.
CHO CH2 OH
KOH
+ HCHO HCOO +

Intramolecular Cannizzaro reaction

CHO NaOH CH2OH
CHO  COONa
O OH
NaOH
Ph CHO  Ph COO
Write the product in the following transformations.

CHO
NaOH conc. H2SO4
? ?
 
CHO
Sol:
O
CHO
NaOH OH conc. H2SO4
O
 
CHO COONa
Write the product in the following transformation.

R
Ca  OH2
?
R CHO 
H
Sol:
R Ca  OH 2 R R
+
R CHO  R COO R CH 2 OH
H H H
Write the products in the following transformations.
CHO
NO 2 O
KOH OD
a) ? b)
?
 D H 
CHO
CHO CHO
O
KOH
c) OH d) + ?
? 
D D 
OMe NO2
__________________________________________________________________________________________________
g) Tollens’ reaction
In the Tollens’ reaction an aldehyde or ketone containing an -hydrogen is treated
with formaldehyde in the presence of Ca  OH 2 or a similar base.
H CH 2 OH
Ca  OH 2
C R + 2 HCHO C R + HCOOH
R C R C
OH
O
The first step is a mixed aldol reaction.
H CH 2OH
C R base C R
R C + HCHO C
O O
The reaction can be stopped at this point, but more often a second equivalent of
formaldehyde is permitted to reduce the newly formed aldol to a 1,3
1,3-diol, in a crossed
reaction If the aldehyde or ketone has several -hydrogens, they can all be
Cannizzaro reaction.
replaced. An important use of the reaction is to prepare pentaerythritol from
acetaldehyde.
CH3CHO + 4
4HCHO
HCHO C  CH2OH4 + HCOOH
Pentaerythritol is a building block for

for the synthesis and production of explosives,
plastics, appliances,, and many other important chemicals.
h) Tishchenko reaction
Tishchenko found that both enolizable and non-enolizable
non enolizable aldehydes can be converted
to the corresponding esters in the presence of magnesium-
magnesium or aluminum alkoxides.
The reaction involves a hydride shift from one aldehyde to another that leads to the
formation of the ester product. This transformation is known today as the Tishchenko
reaction.
O O
1 1 1
R catalyst R R
H O
2 2 2
R R R
Mechanism
Al(OR' )3 Al(OR' )3
O O R O
Al  OR ' 3
O
R H R H H R H
O R
 Al  OR ' 3
O H H
R O R
i) Perkin reaction
The condensation of aromatic aldehydes with the anhydrides of aliphatic carboxylic
esence of a weak base to afford  ,β-unsaturated
acids in the presence unsaturated carboxylic acids is
known as the Perkin reaction or Perkin condensation.
R2
O O R1
2 O
2
R  
2
1 + R R base
R H O O O
O O 
aldehyde
anhydride β-alkoxide intermediate
R2
R1 O
OH
,   Unsaturated
carboxylic acid
Mechanism
O O O O R1
H
H base O
H3 C O base O CH2
H
O
O O
O O
1 O
R O
O R1
base
1 H
R O
1 1
R O R O
OAc OAc
O O O
O O O O
H , base
O O
O O O
H2O  AcOH
1
R O
OH
,   Unsaturated acid
The general features

tures of the transformation are
i) The aldehyde component is most often aromatic, butbut aliphatic aldehydes with no -
hydrogens as well as certain ,- unsaturated aldehydes can also be used.
used
ii) The reaction is more facile and gives higher yield of the product when the aromatic
electron withdrawing substituents.
aldehyde has one or more electron-withdrawing substituents
iii) Aliphatic aldehydes are not suitable for the reaction, since they often give enol
acetates and diacetates when heated with acetic anhydride.
anhydride
iv) The anhydride should be derived from an aliphatic carboxylic acid, which has at least
position (if there is only one -hydrogen atom, a β-
two hydrogen atoms at their -position
hydroxy carboxylic acid is obtained)
obtained).
v) The weak base is most often the alkali metal salt of the carboxylic acid corresponding
to the applied anhydride or a tertiary amine (e.g., Et3N ).
Ex:
O
O O
CH3
1) +
H 3C O CH3
i) AcONa ii) H3O
COOH
O O
i) H3C
H 3C CH3
H O
2) COOH
O O O
O ii)
H3 C
ONa
Give products in following reaction.

reaction
O
C O O
H H2O
i) CH3COOK, 
+ H 3C C O C CH3 ? ?

OH ii) H3O, 
Sol:
O O
C O O CH CH C OH
H
i) CH3COOK, 
+ H 3C C O C CH3
OH ii) H3O,  OH
  H2O
C
O O
Give products in following reaction

reaction.
O
CH CH C CH3 O O
i) AcONa
a) + H 3C C O C CH3 ?
ii) H3O
i) CH3CH2COOCOCH2CH3
b) H
?
C
O ii) CH3CH2COONa
O
 Ac 2 O i) H2O,OH
c) O ? ?
AcONa,  ii) H, 
O
__________________________________________________________________________________________________
j) Reformatsky reaction
The Reformatsky reaction is an organic reaction which condenses aldehydes or
ketones, with -halo
halo esters, using metallic zinc to form -hydroxy
hydroxy-esters.
Zn Br
O O
3
O O
1 2 + Br R  Zn 3
R R O 1 R
R 2 O
R
 H2O  H
H
O O
3
R
1 O
R 2
R
Mechanism
Zn
Zn ZnBr
O O O
Br
Br
OEt OEt OEt
zinc enolate
ZnBr ZnBr ZnBr

O O O O O
RCHO
OEt R OEt R OEt
H2O
OH
H O
R OEt
Ex:
O O OH O
i) Zn-ether
1) + Br CH2 C OEt H3 C CH CH2 C OEt
H3 C H
ii) H  or  NH4Cl, H2O
O CH3
Zn, ether
2) + BrCH2COOC2H5 H3 C C CH2 COOC2 H5
H3 C CH3
OZnBr
H3O
CH3
H3 C C CH2 COOC2 H5
OH
k) Benzoin condensation
Upon treating certain (but not all) aromatic aldehydes or glyoxals (-keto
( aldehydes)
with cyanide ion ( CN ), benzoins (-hydroxy-ketones
ketones or acyloins) are produced in a
reaction called the benzoin condensation.
O O O H
catalyst
C + C R
R H R H R OH
Benzoin
R = aryl, catalyst: NaCN, KCN
KCN.
Mechanism
H
H O O H HO H
O C CN R C H R C C O R R
R CN CN R CN O
O H O H
CN
R R R
R OH CN OH
Benzoin
The condensation involves the addition of one molecule of aldehyde to the C O group
of another. One of the aldehydes serves as the donor and the other serves as the
acceptor. Some aldehydes
alde can only be donors (e.g. dimethylaminobenzaldehyde)
dimethylaminobe or
acceptors, so they are not able to self-condense,
self condense, while other aldehydes (benzaldehyde)
can perform both functions and are capable of self condensation.
self-condensation
Ex:
KCN O
1)
H EtOH, H2O O
O O
O OH
CHO CHO
OH
H O
KCN
2) + H3 C CH
H C NO 2
EtOH, H2O
CH3 NO 2
l) Benzilic acid rearrangement

atment with base (e.g., NaOH), -diketones
Upon treatment diketones rearrange to give salts of
-hydroxy
hydroxy acids. This process is called the benzilic acid rearrangement.
O OH OH
R R
R OH R H HO
R' R' R'
O O O
  diketone   hydroxy acid salt   hydroxy acid
Mechanism
R OH OH OH
R
O O Proton O
OH O R
transfer R'
O R
R' R' O O R' O
  Hydroxy acid salt
tetrahedral
intemediate
The general features of reactions
reaction
i) The reaction takes place with both aliphatic and aromatic -diketones and -
keto aldehydes. Usually diaryl diketones undergo benzilic acid rearrangements
in excellent yields, but aliphatic -diketones that have
ve enolizable -protons give
low yields due to competing aldol condensation reactions.
ii) Cyclic -diketones
diketones undergo the synthetically useful ring-contraction
ring benzilic
acid rearrangement reaction under these conditions. When alkoxides or amide
anions are used in place of hydroxides, the corresponding esters and amides
are formed. This process is called the benzilic ester rearrangement.
O
OH OH
OH H
COO COOH
O
iii) Aryl groups tend to migrate more rapidly than alkyl groups. When two different
aryl groups are available, the major product usually results from migration of
the aromatic ring with the more powerful electron-withdrawing group
withdrawing groups.
Ex:
HO COOH
O
O C O
i) KOH
1) O
ii) H
O
O
O
OH
OH
2)

COO
O
O O OH
OH
3) Ph C C Ph Ph C COO
Ph
O O OH
i) Ba  OH2
4) MeO C C NO2 HOOC C Ph NO2
ii) H3O Ph OMe
ii) HCl i) EtONa
OH
EtOOC C Ph NO2
Ph OMe
Reduction of aldehyde and ketones

a) Hydride transfer reductions (Refer alcohols)
When treated with a hydride reducing agent, such as LAH or sodium borohydride
 NaBH 4  , aldehydes and ketones are reduced to alcohols.
O OH O OH
i) LAH NaBH4 ,
R R ii) H2O R R R R MeOH R R
Predict the major product for each of the following reactions

reactions.
O
O
i) LAH H NaBH4 ,
a) ? b) ?
ii) H2O MeOH
O
O
NaBH4 ,
c) i) LAH d) ?
? MeOH
ii) H2O
b) Wolff-Kishner
Kishner reduction
The deoxygenation of aldehydes and ketones to hydrocarbons via the corresponding
hydrazones or semicarbazones under basic conditions is known as the Wolff
Wolff-Kishner
reduction.
NNH 2 H H
KOH / H2O

a hydrazones (82 %)
Mechanism
H H H
H
N N N
N H N N O H N N
OH H H
OH
H H O H H N N
H H
The general features of the reaction are

i) Esters, lactones, amides, and lactams are hydrolyzed under the reaction
conditions.
ii) Sterically hindered carbonyl compounds are deoxygenated more slowly than
unhindered ones, so higher reaction temperatures are required.
iii) Can’t be used ffor , β-unsaturated
unsaturated carbonyl compounds.
Ex:
NH2
O N H H
H
H2 N NH2 KOH / H2O
1) + N2
H2O 
 80 % 
O
i) NH2 — NH2
2) H3 C CH3
H ii) EtONa, 
CHO i) NH2 — NH2

3)
ii) NaOH, 
two step procedure below, and draw a mechanism for its formation
Predict the product of the two-step
O
i) H, H2N NH2 ,  H2O
?
ii) KOH / H2O, 
__________________________________________________________________________________________________
c) Clemenson reduction
Ketones and aldehydes are converted to the corresponding alkanes upon refluxing for
acid, amalgamated zinc (Zn/Hg), and a
several hours with 40% aqueous hydrochloric acid,
hydrophobic organic co-solvent
co solvent such as toluene. This method of converting a carbonyl
group to the corresponding methylene group is known as the Clemmensen reduction.
O H
Zn  Hg  /organic solvent H
R R' 40% HCl  aq. or dry HX R R'

aldehyde or ketone X  Cl or Br alkane
Mechanism
R
R
R '  ZnO R R'
O
O
R'
Zn
Zn Zn
H
H
H H R R'
H
R R'  Zn2 Zn
The general features of the reaction are

i) sensitive substrates and polyfunctional ketones
Clemmensen reduction of acid-sensitive
is rarely successful in yielding the expected alkanes.
ii) Selective reduction of aldehyde or keto groups is not possible by this methods
on compounds containing other functional groups which can be reduced by
metal and acids.
Ex:
O
Zn — Hg
1)
conc.HCl
OH OH
OCH3 OCH3
Zn /Hg
2)
HCl
CH3
H O
Oxidation
I. Mild oxidizing agents
a) Tollen’s test
Tollen’s reagent is Ag in aqueous ammonia or ammonical silver nitrate  AgNO3  NH4OH .
AgNO3  NH4OH AgOH  NH4NO3
2 AgOH Ag 2O  H2O
Ag 2O  2NH4OH 2  Ag  NH3 2  OH  3H2O

soluble 
O O
+ 2 Ag  NH3 2 OH 2 Ag  s  + + H2O + 3 NH3
R H R ONH 4
To oxidize one mole of R — CHO, two moles of AgNO3 must be used.
Only AgNO3 can be used to oxidise R — CHO to R — COO but silver mirror is not
clearly observed.
Eº/Ag / Ag 0.8V
Eº/  Ag  NH3 2  / Ag 0.15V
Ag is a stronger oxidizing agent than  Ag  NH3 2  as indicated by standard

reduction potential values.
If Ag is used for the oxidation,

oxidation, the reaction is vigorous which does not allow formation
of silver mirror. As  Ag  NH3 2  is a milder oxidizing agent it permits the slow
deposition of Ag along the sides of the test tube.

The Ag produced
uced will be deposited on the wall of the test tube forming a mirror so this
test is called as silver mirror test.
Simple ketones do not give positive Tollens test.
The following compounds will give positive Tollens test.

O
H C OH CO2  2Ag 
O O
H C OEt HO C OEt + 2Ag 
(R = aliphatic (or) aromatic)

R H
O O
-hydroxy
-hydroxy ketones HO , HO O
OH
CH2 R CH2 CH2
OH OH OH
OH
O
OH
OH
catechol resorcinol quinol
OH OH H
OH
HO OH OH
HO OH
OHH
pyrogallol phloroglucinol hydroxyquinol
CHO CHO
CHO COOH
glyoxal glyoxalic acid
R NH OH R N O + 2 Ag 
Ag
R C CH R C C Ag
1-alkyne black ppt.
b) Fehling’s test
Fehlings’ reagent is complex of Cu2 in aqueous sodium tartrate.
tartrate
In this test the presence of aldehydes but not ketones is detected by reduction of the
deep blue solution of copper(II) to a red precipitate of insoluble copper oxide.
O O
Fehling reagent
+ Cu2O
R H  R O
red ppt.
aldehydes
Fehling solution A
CuSO4  NaOH Cu  OH 2  Na 2SO4
Fehling solution B
COOK
CHOH
CHOH
COONa
Sodium potassium salt of tartaric acid (Rochelle salt).
Fehlingsolution (A + B)
B
OOC HO OOC COO

CH OH CH COO CH O O CH
+ Cu  OH2 + Cu
CH OH CH COO CH O O CH
OOC HO OOC COO
O O
Fehling reagent
+ Cu2O 
R H R OH  red 
OH O
Fehling reagent
+ Cu2O 
O O
O
Fehling reagent
H C OH CO2  Cu2O 
Fehling reagent
R NH OH R N O + Cu2O 
O OH
Fehling's reagent COO + Cu2O
O
Aromatic aldehydes
es, glyoxal, glyoxalic acid do not give positive Fehling test, and all
remaining compounds discussed in Tollen’s test give positive Fehling test.
c) Benedict test
volume mixture of aqueous solution of CuSO4 and sodium citrate. Here
It is an equi-volume
sodium citrate is the complexing agent. Benedict's solution is a deep
deep-blue alkaline
solution.
OH
HOOC CH2 C CH2 COOH

COOH
citric acid
This reaction is similar to Fehling test.

R R
Benedicts solution
+ Cu2O + 3H
3 H2O
H O O O
II. Strong oxidizing agents

KMnO4 and K2Cr2O7 /H2SO4 are strong oxidizing agents and can cleave ketones to
carboxylic acids provided harsh conditions.

O O
i) KMnO4 , OH
R H R OH
ii) H3O
aldehyde
Popoff's rule
Popoff's rule states that during the oxidation of an unsymmetrical ketone, the cleavage of the
C—CO bond is such that the keto group always stays with the smaller alkyl group.
O
KMnO4
CH3CH2CH2COOH  CO2
H,  +
CH3COOH  CH3CH2COOH
major
O
COOH
KMnO4
+ CO2
H, 
KMnO4
no reaction
H, 
III. Oxidation with SeO2

Selenium dioxide oxidizes reactive methylene group adjacent to carbonyl carbon at room
temperature to form dicarbonyl compounds.
CH3CHO + SeO2 H C C H + Se + H2O
O O
 glyoxal 
O O
O
SeO2
Schiff’s test
Aldehydes restore the colour of Schiff’s reagent. Schiff’s reagent is prepared by passing
sulphur dioxide into a solution of the dye fuchsin (magenta). The solution becomes colourless
due to the formation of an addition product. An aldehyde abstracts sulphurous acid from the
Schiff’s reagent and restores the pink colour.
R H
Schiff’s reagent pink/magenta.
Ketones (except acetone) does not give pink (or) magenta all aldehydes give pink (or) magenta.
CONJUGATE ADDITION REACTIONS
Aldehydes and ketones that possess ,unsaturation, exhibit unique reactivity at the -
position.
O O O
H H H
Notice that two of the resonance contributors exhibit positive charges. In other words, the
compound will have two electrophilic positions, the carbon of the carbonyl group as well as
the-position.

O

 H
two electrophilic positions
O or O
Nu Nu
conjugate 1,4-addition direct 1,2-addition
The way thatt nucleophiles react depends on

i) The conditions of the reaction
ii) The nature of the ,-unsaturated carbonyl compound
iii) The type of nucleophile
O NC OH
NaCN, HCN
5-10 C
cyanohydrin
(direct addition to carbonyl)
O O
NaCN, HCN
80 C CN
conjugate addition product
Direct addition to the carbonyl group turns out to be faster than conjugate addition.
O O NC OH
CN CN
CN
cyanohydrin
Conjugate addition is essentially an irreversible reaction, so once a molecule of enone has

been converted to conjugate addition product, its fate is sealed: it cannot go back to enone
again.
Kinetic and thermodynamic control

contr
i) The product that forms faster is called the kinetic product.
ii) The
he product that is the more stable is called the thermodynamic product.
product
iii) Conditions that give rise to the kinetic product are called kinetic control.
control
iv) Conditions that give rise to the thermodynamic product are called thermodynamic
control.
O HCN, KCN O
160 C
CN
75% yield
O OH
i) BuLi,  70 C to  20 C
H ii) H2O Bu
Hard and soft nucleophiles

Hard nucleophiles Borderline Soft nucleophiles
F, OH, RO, SO24 , Cl N3 , CN I, RS, RSe, S2
H2O, ROH, ROR', RCOR ' RSH, RSR ', R 3P

NH3 , RMgBr, RLi RNH2 , RR' NH, Br alkenes, aromatic rings
Hard/soft—direct/conjugate
direct/conjugate addition
i) Hard nucleophiles tend to react at the carbonyl carbon (hard) of an enone.
enone
ii) Soft nucleophiles tend to react at the b-carbon
b carbon (soft) of an enone and lead to conjugate
addition.
O
HO Me
MeMgBr
Et2O
Me Me
O O
MeMgBr
CuCl  0.01 eq.
Et2O Me
Me
Me
i) Bu2CuLi
CHO CHO
ii) H3O 80% yield
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or
another nucleophile to an ,-unsaturated
 carbonyl compound.
O i) KOH O O O
ii) H
H
O iii) H3O O
Miscellaneousreactions
O
4
4NH
NH3
6  CH2  N4 
 6 
H H
Hexa-methylene-tetra-amine
 Urotropine 
O C6 H 5
2NH3
3 H 5 C6 CH N CH N CH C6 H 5
H 5 C6 H
(hydrobenzamide)
O NH2 O
2 NH3
H 3C C CH2 C CH3
H 3C CH3
CH3
O
allowed to stand O O
H H g  at room temperature
O
O
conc.H2SO4 O O
H H  aq 
O
 60 % 
HO OH
O O O
OH OH
3 + 3H2O + 3H2O
H H O
OH HO
O
evaporate to
CH2 O
H H  aq  dryness n
n  6  50
paraformaldehyde
(white solid)
O
OH
C6H12O6
H H formose
(mixture of
carbohydrates)
O O O
conc.H2SO4
4
H 3C H 0 C or dry HCl
O O
(metaldehyde)

02536595d9d9d-Aldehydes and Ketones

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02536595d9d9d-Aldehydes and Ketones

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A LDEHYDES AND K ETONES

SYNTHESIS OF ALDEHYDES AND KETONES

II. From alkenes

b) Alkenes can be converted to aldehydes or ketones on dihydroxylation followed by

chain terminal alkenes > straight-chain

Terminal alkenes react much faster than internal or 1,1-disubstituted

III. From alkynes

d) Oxidation with cold.alk. KMnO4

e) Oxidation with SeO2

IV. From alkyl halides

VI. From carboxylic acids

Aldehydes can be synthesized

Ketones can be synthesized

If a mixture of calcium salts is used, mixed ketones are obtained.

R1CO2 2 Ca + R2CO2 2 Ca 2R1COR 2 + 2CaCO3

b) Keto carboxylic acids undergo decarboxylation on heating.

c) Glycidic acids give aldehydes on decarboxylation.

Reaction with alkyl lithium

VII. From acid chlorides

The reaction is catalysed by palladium on barium sulfate,, poisoned with quinolone.

b) Acyl halides can also be reduced to aldehydes by treatment with DIBAL-H

Reaction with organometallic

Identify the products in the following reactions.

IX. From nitriles

Reaction with Grignard reagent

R ' MgX H3O

Give the products of following reaction.

NBS NaCN i) SnCl2 / HCl

NBS NaCN i) SnCl2 /HCl

DMF ii) H3O

Give the products of following reaction.

i) CH3CH2MgBr DIBAL-H conc.H2SO4

Give the products of following reaction.

Preparation of aromatic aldehydes and ketones

Because of this hydrogen bonding, ketones and aldehydes

Physical properties of some representative ketones and aldehydes

3- pentanone Diethyl ketone CH3CH2COCH2CH3 –41 101 0.81 4.8

2-hexanone CH3CO  CH2 3 CH3 –57 127 0.83 1.6

electron donating group.

Mechanism of nucleophilic addition under basic conditions

Mechanism of nucleophilic addition under acidic conditions

Very powerful electrophile

Cyclopropanone on conversion to its hydrated form, gets relieved from angle

By removing water as it is formed, the reaction can be forced to completion.

acyclic acetal formation

cyclic acetal formation

O TsOH EtO OEt

Draw a plausible mechanism for the following transformation

Draw a plausible mechanism for each of the following transformations.

Predict the product(s) for each reaction below

Draw a plausible mechanism for the following transformation

II. Nitrogen nucleophiles

The rate of imine formation as a function of pH.

2,4 DNP are yellow or orange crystalline solids, so

Predict the major product for each of the following reactions

Predict the product of each of the following reactions.

4) Aldoximes give cyanides as the exclusive product.

Stork enamine reaction

Write the products in the following transformation.

III. Sulfur nucleophiles

When treated with Raney nickel, thioacetals undergo desulfurization, yielding an

b) Bisulfite addition compounds

IV. Carbon nucleophiles

Predict the major product of each reaction below