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Unit 4: Name Reactions
Introduction:
A name reaction is a chemical reaction named after its discoverers or developers.
Well known examples include the Wittig reaction, the Claisen condensation, the Friedel-
Crafts acylation, and the Diels-Alder reaction etc. Among the tens of thousands of organic
reactions that are known, hundreds of such reactions are well-known enough to be named
after people. Books have been published devoted exclusively to name reactions; the Merck
Index, a chemical encyclopedia, also includes an appendix on name reactions.
As organic chemistry developed during the 20th century, chemists started
associating synthetically useful reactions with the names of the discoverers or developers; in
many cases, the name is merely a mnemonic. Some cases of reactions were not really
discovered by their namesakes are known. Examples include the Pummerer rearrangement,
the Pinnick oxidation and the Birch reduction.
1.1 Claisen Condensation
Introduction:
The Claisen condensation (different from the Claisen rearrangement) is a carbon–
carbon bond forming reaction that occurs between two esters or one ester and
another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-
diketone. It is named after Rainer Ludwig Claisen, who first published his work on the
reaction in 1887.
Statement:
Base-catalyzed condensation of an ester containing an α-hydrogen atom with a
molecule of the same ester or a different one to give β-keto esters is known as
Claisen condensation
General reaction:
The Condensation reaction in which, two molecules of esters condense with each
other in the presence of a strong base like sodium alkoxide, produce β-keto ester is called
Claisen Condensation reaction.
Example: The molecule of ethyl acetate condenses with other molecule of ethyl
acetate in the presence of sodium ethoxide to form ethyl acetoacetate a β-keto ester.
CH3 O
O
CH2 CH3
NaOC2H5
H3O+ CH3
O
O
O
CH2CH3C2H5OH
1.
2.+2
Ethyl acetate Ethyl acetoacetate Ethanol
Important features:
The base used must not interfere with the reaction by
undergoing nucleophilic substitution or addition with a carbonyl carbon. For this reason, the
conjugate sodium alkoxide base of the alcohol which is formed as a byproduct. (e.g. sodium
ethoxide if ethanol is formed) is often used, since the alkoxide is regenerated. However some
other catalysts as Ph3C-Na+ also can be used. But most important thing is to have the at least
one of the reagents must be enolizable i.e. should have an α-proton and be able to
undergo deprotonation to form the enolate anion.
Note that the reaction requires a stoichiometric amount of base. i.e. one gram
equivalent of sodium mixed with little ethanol is used as a base. More alcohol is not needed
as ethanol is produced during the reaction itself. The formation of the carbanion is an
essential feature of the reaction. It helps to drive the equilibrium to the product side.
It is also necessary to have substrates with more than one hydrogen, as Claisen
condensation does not work with substrates having only one α-hydrogen because of the
driving force effect of deprotonation of the β-keto ester in the last step.
If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone
or a β-ketonitrile is obtained, respectively.The use of stronger bases, e.g. sodium amide or
sodium hydride instead of sodium ethoxide, often increases the yield.The intramolecular
version is known as Dieckmann Condensation
Mechanism:
� In the first step of the mechanism, an α-proton is removed by a ethoxide anion
which acts as a strong base from one ester molecule, resulting in the formation of an
carbanion intermediate which is stabilized by resonance i.e. by the delocalization of electrons
in the form of an enolate anion ( en= double bond, olate= oxygen carrying negative charge)
, which is made relatively stable.
CH2
O
O
CH2 CH3
C2H5O-
H
H2C O
O
CH2 CH3 CH2 O
O
CH2 CH3
ethoxide ethyl acetate
-
-
carbanion enolate ion
� In the second step, the carbanion intermediate attacks the carbonyl carbon of
the (other) ester.
CH3
O
O
CH2 CH3
H2C O
O
CH2 CH3
CH2
O
O
CH2 CH3
O
O
CH3
CH3CH2
ethyl acetate
-
carbanion
-
� The alkoxy group is then eliminated resulting in regeneration of the alkoxide.
CH2
O
O
CH2 CH3
O
O
CH3
CH3CH2
-C2H5O-
CH2
O
O
CH2 CH3CH3
O-
Ethyal acetoacetate
� Aqueous acid (e.g. sulfuric acid or phosphoric acid) is added in the final step
to neutralize the enolate and any base still present. The newly formed β-keto ester or β-
diketone is then isolated.
C2H5O- CH3COOC2H5 C2H5OH -CH2COOC2H5
CH3COOC2H5
-CH2COOC2H5
CH3 OC2H5
O
CH2COOC2H5
C CH3COCH2COC2H5
-C2H5OH
H3O+
ethoxide ethyl acetate carbanion
+ +
ethyl acetatecarbanion Mechanism simplified
Synthetic applications:
1. Claisen condensation is applied in the synthesis of 3-hydroxy-isoxazoles where,
the -keto ester is cyclized with hydroxyl amine to give 3-hydroxy -isoxazole.
R1
O
R2
O
O
RNH2OH
H2 O ON
OHR2
R1
b ketoester 3-hydroxy isoxazole
2. A thioanalog of the β-keto ester obtained by Claisen condensation is cyclised to
get the isothiazolyl piperidine derivative.
N
O
O O
MeO
OEt N
O
SN
ROH
MeO
4-(2-Ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid methyl ester
1. Aq. NH3,
2. H2S,HCl,EtOH
3. I2,K2CO3
4-(3-Hydroxy-4-alkyl-isothiazol-5-yl)-piperidine-1-carboxylic acid methyl ester
3. An early synthesis of cholesterol involved the "mixed Claisen reaction"
CH3
HO
H O
O
C2H5NaOC2H5
C2H5OH
CH3
HO
OH
+
4. The short total syntheses of justicidin B and retrojusticidin B
5. Synthetic approach to prepare (+) -methyl -7-benzopederate
1.2 Perkin reaction
Introduction:
The Perkin reaction is an organic reaction developed by William Henry Perkin that
is used to make cinnamic acids. It gives an α,β-unsaturated aromatic acid by the aldol
condensation of an aromatic aldehyde and an acid anhydride, in the presence of an alkali salt
of the acid. The alkali salt acts as a base catalyst, and other bases can be used instead.
Statement:
Formation of α,β-unsaturated carboxylic acids by condensation of aromatic
aldehydes and acid anhydrides in the presence of an alkali salt of the acid is known as Perkin
reaction.
General reaction:
Aromatic aldehyde reacts with aliphatic acid anhydride in presence of the sodium
salt of the aliphatic acid to give α -β unsaturated acid.
Example: Benzaldehyde when treated with acetic anhydride in presence of sodium
acetate gives α -β unsaturated acid cinnamic acid.
H
OCH3
O
O
OCH3
CH3COONa CH
CH
OH
O
+
Cinnamic acidAcetic unhydrideBanzaldehyde
Important features:
Perkin's reaction is a kind of condensation reaction. The reaction takes
place in the presence of suitable basic catalyst. Basic catalyst used in this reaction is the
alkali salt of the same aliphatic acid whose anhydride is used for the condensation. The
reaction depends only on the presence of a CH2 group in the α-position of the anhydride. The
aromatic aldehyde reacts only with the anhydrides and not with the acid anions.
Mechanism :
� First step is the formation of carbanion ion from the acetic anhydride due to
abstraction of α-proton by acetate ion from salt.
i.e. sodium acetate ionizes into sodium and acetate ion.
CH3COONa CH3COO- Na++
� This acetate ion abstracts the activated α-proton from the acetic anhydride to
produce carbanion ion, which is stabilized by resonance as enolate ion.
CH3COO CH2 O
O
OCH3
H CH2
O
O
OCH3
CH2
O
O
OCH3
Acetic anhydride
_
carbanion ion
_
enolate ion
_
� In second step the carbanion attacks the aromatic aldehyde molecule. The
electron rich negatively charged carbon from carbanion intermediate attacks the polar
carbonyl group. The carbon from carbonyl group in the polar carbonyl group is electron
deficient as compared to the more electronegative oxygen atom which is rich in electron
density. This attack leads to the formation of alkoxide ion where the negative charge lies on
oxygen, which abstracts proton from the reaction medium to form an adduct.
H
O
Benzaldehyde
CH2
O
O
OCH3
H+
OH
HH
HO
O
OCH3
adduct
_
carbanion ion
+
� This Adduct on dehydration in presence of acetic anhydride, looses water
molecule to give an anhydride which is anhydride of two acids out of which one is aromatic
and other one is aliphatic acid. This mixed acid anhydride undergoes hydrolysis to give α -β
unsaturated acid.
OH
HH
HO
O
OCH3
-H2OCH
CH
O
O
OCH3
H2 OCH
CH
O
OH
mixed acid unhydride Cinnamic acid
Synthetic applications:
1. Perkin's reaction is used in the synthesis of coumarin.
OH
H
O
CH3
O
O
OCH3
CH3COONa
O O
CH3COOH H2 O+
Acetic unhydride
+ +
salicylaldehyde coumarin acetic acid water
2. Synthesis of (E)-3-(3,5-Dimethoxy-phenyl)-2-(4-methoxy-phenyl)-acrylic acid
3. Synthesis of (E)-4-Chloro-4,4-difluoro-3-phenyl-but-2-enoic acid
1.3 Mannich Reaction
Introduction:
The reaction is named after chemist Carl Mannich. The Mannich reaction is an
example of condensation reaction which includes nucleophilic addition of an amine to
a carbonyl group followed by dehydration to the Schiff base. The Schiff base is
an electrophile which reacts in the second step in an electrophilic addition with a compound
containing an acidic proton. Thus Mannich reaction is considered a condensation reaction of
three entities as aryl alkyl ketone, formaldehyde and an amine.
Statement:
The condensation of a compound having one or more active hydrogen atoms with
formaldehyde and ammonia or a primary or secondary amine forming a β-aminocarbonyl
compound is known as Mannich reaction.
General reaction:
Generally, in Mannich reaction, Aryl alkyl ketone reacts with formaldehyde and
secondary amine to give β-amino ketone.
Example: Acetophenone, formaldehyde and dimethyl amine condense to get the 3-
dimethylamino-1-phenyl-propan-1-one ( β-amino ketone)
O
HH
ON
CH3H
CH3
O
N
CH3
CH3
acetophenone formaldehyde dimethyl amine
a
b
b amino ketone
+ +
Important features:
In the Mannich reaction, primary or secondary amines or ammonia, are employed
for the activation of formaldehyde. However, if ammonia or primary amines are used, the
first formed Mannich base still carrying hydrogen on the nitrogen can itself participate further
in the reaction which will lead to more complex products. Tertiary amines lack an N–H
proton to form the intermediate enamine. Hence preference is given to secondary amine. α-
CH-acidic compounds (nucleophiles) include carbonyl compounds, nitriles, acetylenes,
aliphatic nitro compounds, α-alkyl-pyridines or imines. It is also possible to use
activated phenyl groups and electron-rich heterocycles such as furan, pyrrole,
and thiophene. Indole is a particularly active substrate; the reaction
provides gramine derivatives. The reaction conditions are often milder as the reaction is
inhibited in strongly basic and strongly acidic solutions. The reaction is third order reaction,
where Mannich base forms more slowly than when the three components are mixed together.
(Such reactions are called multicomponent reactions MCR)
Mechanism :
� There is formation of an iminium ion from the amine and the formaldehyde.
There is attack of unshared pair of electrons on the nitrogen on the carbonyl carbon from
formaldehyde, which is followed by protonation and elimination of water to yield the
iminium* ion.
*(Ammonia is NH3, amine is -NH2, imine is =NH, iminium is =N+
H H
ON
MeH
MeH
NO
H Me
Me
C H
H
NOH
H
Me
Me
C
H
N
H Me
Me
C+
formaldehyde dimethyl amine
..+ ..
-OH- +
imminium ion
_
� Simultaneously, the acetophenone which has keto enol tautomerism is
deprotonated to get the carbanion.
O
CH2Ph
H
O
CH2Ph
O
CH2Ph
H
-H+ _
keto enol
Acetophenone carbanion � Electrophilic imminium ion attacks the carbanion to form the Schiff base i.e.
β-amino ketone.
H
N
H CH3
CH3
CO
CH2
Ph
O
CH2
PhH
N
H CH3
CH3
C+
imminium ion
+_
carbanion B amino ketone Synthetic applications:
The Mannich-Reaction is employed in the organic synthesis of natural compounds
such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone). Other applications
are in agro chemicals such as plant growth regulators, paint- and polymer
chemistry,catalysts and main mechanism of formalin tissue crosslinking.
The Mannich reaction is also used in the synthesis of medicinal compounds
e.g. rolitetracycline (Mannich base of tetracycline), fluoxetine (antidepressant), tramadol
and tolmetin (anti-inflammatory drug)and azacyclophanes.
1. The total synthesis of (±)-aspidospermidine
2. The total synthesis of (+)-croomine.
3. Synthesis of (4-Methoxy-phenylamino)-(2-oxo-cyclohexyl)-acetic acid ethyl ester
4. Synthesis of 3-(2-oxo-cyclohexyl)-5,5-diphenyl-morpholin-2-one
5. Synthesis of 4-(4-Methoxy-phenylamino)-4-(4-nitro-phenyl)-butan-2-one
1.4 Knoevengel Condensation
Introduction:
The Knoevenagel condensation reaction is an organic reaction named after Emil
Knoevenagel. It is a modification of the aldol condensation. A Knoevenagel condensation is
a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by
a dehydration reaction in which a molecule of water is eliminated (hence condensation). The
product is often an alpha, beta unsaturated.
Statement:
It is condensation reaction between an aldehyde or a ketone with a compound having
an active methylene group in presence of a base to yield an unsaturated compound is called
Knoevenagel reaction.
General reaction:
The condensation of aldehydes or ketones usually not containing an α-hydrogen with
the compounds of the form Z-CH2-Z' or Z-CHR-Z' is called Knoevengel condensation
reaction. where, Z and Z' may be CHO,COR,COOH,COOR, CN, NO2, SOR,SO2R,SO2OR
etc. In short, it is condensation of an aldehyde or ketone with active methylene compound in
presence of weak base to form α-β unsaturated compound.
O
R R
base
-H2O
z z
H HR
z z
R+
aldehyde or ketone active methylene compound unsaturated compound
Example:
Benzaldehyde condenses with diethyl malonate in the presence of a base pyridine in
benzene to give cinnamic acid on hydrolysis and dehydration.
CHO COOEtCH COOEt
COOEtC
CH COOH
COOHC
CH
CH-COOH
H2C
COOEt
+
pyridine/benzene-H2O
hydrolysis
Cinnamic acid
heat
-CO2
benzaldehyde diethyl malonate
Important features:
The active methylene compound is diethyl amlonate, ethyl acetoacetate, ethyl
cyanoacetate, phenyl acetonitrile, benzyl ketones, aliphatic nitro compounds etc. When
Z=COOH, the reaction always proceeds via decarboxylation. If a strong base is used the
reaction can be performed on compounds possessing only single Z. i.e. CH3Z or RCH2Z.
Other active hydrogen compounds can also be employed are CHCl3, 2-methylpyridine,
terminal acetylenes, cyclopentadienes etc.
The aliphatic aldehyde shows Michael reaction in presence of excess of active
methylene compound. Therefore, Knoevenagel reaction is more useful for the condensation
of aromatic aldehyde.
Mechanism:
� Step I: In the first step, the carbanion is formed in a base catalysed removal of
proton from active methylene group i.e from diester diethyl malonate which is stabilized by
resonance.
B
COOEt
HC
COOEt
COEt
HC
COOEt
O
COOEt
HC
COOEt
H
diethyl malonate
+_
carbanion
� Step II: In the second step, there is a nucleophilic attack of carbanion on
carbonyl carbon from benzaldehyde. Due to the polar nature of the carbonyl group, the attack
takes place at electron deficient carbon atom from the carbonyl group. This on protonation
forms an adduct i.e. 2-benzylidene-malonic acid diethyl ester. This undergoes hydrolysis and
decarboxylation to give cinnamic acid.
CH
COOHCH
COOEt
HC
COOEt
CH
O
COOEt
COOEtC=O
HH
C
CH COOEt
COOEtC
1. hydrolysis
Cinnamic acid
_
carbanion
+ H+
_
-H2O
Unsaturated diester
2. -CO2
Synthetic applications:
The reaction has wide applications due to the great scope of active methylene
compounds.
1. synthesis of 5-[1-{4-[2-(Methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-meth-(E)-
ylidene]-thiazolidine-2,4-dione
2. Synthesis of 2Z,4E)-2-Cyano-5-phenyl-penta-2,4-dienoic acid ethyl ester
CN
COOEtCOOEt
CNCHO ethyl ammonium nitrate
RT 10h,+
3.Synthesis of hirsutine
4. Synthesis of (±)-leporin A
5. Synthesis of (±)-gelsemine
6. Synthesis of 5-[(E)-2-{3-[3-(1-Methanesulfonyl-1-methyl-ethyl)-naphthalen-1-
yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-propenyl]-3-methyl-[1,2,4]oxadiazole
1.5 Reformatsky Reaction
Introduction:
The Reformatsky reaction (sometimes spelled Reformatskii reaction) is
an organic reaction which condenses aldehydes (or ketones) with α-halo esters, using a
metallic zinc to form β-hydroxy-esters. It was discovered by Sergey Nikolaevich
Reformatsky.
Statement:
Condensation of aldehydes or ketones with organozinc derivatives of α-halo esters to
yield β-hydroxy esters: is called Reformatsky reaction.
General reaction:
Formation of β-hydroxy ester from an aldehyde or ketone on condensation with α–
bromo ester in presence of metalic zinc in dry ether or benzene is called Reformatsky
reaction.
O
R1 R2Br
O
OR3
R1
OH
OR3
O
R2
Zn+
Example:
Benzaldehyde on condensation with ethyl bromoacetate in the presence of zinc gives
Ethyl-3-hydroxy-3-phenylpropanoate.
Br
O
OEtO
H
Zn
O O
OEt+
Ethyl-3-hydroxy-3-phenyl propionatebenzaldehyde ethyl bromo acetate
Important features:
Halide is usually a alpha halo ester or derivative of α-halo ester like
(RCHBrCH+CHCOOEt), α-halo nitriles, α-halo ketones, α-halo N,N-disubstituted amides or
α-halo carboxylic acid salt. The reaction also can be carried out with other metals as In, Mn
and with certain other compounds including Et2O, THF and 1,4-dioxane. Usually when the
product is an alcohol due to hydrolysis reaction, we get the olefin due to elimination when the
catalyst zinc is replaced by Bu3P. Since Grignard reagents cannot be formed from esters, this
reaction is very useful, though there are some competing reactions and yields are sometimes
low.
Mechanism:
The reaction can be regarded analogous to Grignard reaction.
� In the first step, the intermediate is derived from zinc and the ester which is
an carbanion ion due to abstraction of bromine from the bromo ester.
BrCH2COOEt CH2COOEt
ZnBr
Zn
OZn
O
Br
Br
OEt
EtO
Zn + ether
a-bromoester
_
+
� The intermediate carbanion is stabilized by resonance as follows:
CH2
O
OEt CH2
O
OEt_
_
� Step II: This carbanion then attacks the carbonyl group of benzaldehyde at
the electron deficient carbon atom and forms an adduct.
CH2COOEtPh
OZnBr
H
CH2COOEtCO
HPh
ZnBr
adduct
+_
benzaldehyde carbanion
+
� Step III: This adduct further on hydrolysis under cold H2SO4, gives β-
hydroxy ester as product.
R'
R
O-ZnBr
CH2COOEtC
cold H2SO4
R'
R
OH
CH2COOEtCBr
OH
adduct
+ Zn+ H2O
b-hydroxy ester
Synthetic applications:
1. Synthesis of dolaproine
2. Synthesis of epothilones
3. Synthesis of C16, C18-bis-epi-cytochalasin D,
4. Synthesis of [5-Benzyl-1 tert-butyloxycarbonyl-4- tert-butyldimethylsilyl -
pyrrolidin-(2E)-ylidene]-acetic acid methyl ester
5. Synthesis of 2-(5-Methoxy-3H-inden-1-yl)-butyric acid methyl ester
1.6 Reimer-Tiemann Reaction
Introduction:
The Reimer–Tiemann reaction is a chemical reaction used for the ortho-
formylation of phenols; with the simplest example being the conversion
of phenol to salicylaldehyde. The reaction was discovered by Karl Ludwig
Reimer and Ferdinand Tiemann.
Statement: Formation of phenolic aldehydes from phenols, chloroform and alkali: The
formylation of the phenol in basic condition with chloroform to produce an aromatic
aldehyde is called Reimer-Tiemann Reaction
General reaction: In this reaction, the phenol undergoes formylation (i.e. conversion into aldehyde or
replacement of H by CHO group) in alkaline medium with chloroform and gives
salicylaldehyde or ortho hydroxyl benzaldehyde.
OH
CHCl3
OH
CHO
3KOH
Phenol o-hydroxy benzaldehyde Important features:
Unlike other formylation reactions this method is conducted in basic solution. Yields
are low, very rarely the products are obtained above 50%. Hydroxides are not readily soluble
in chloroform, thus the reaction is generally carried out in a biphasic solvent system. In the
simplest sense this consists of an aqueous hydroxide solution and an organic phase containing
the chloroform. The two reagents are therefore separated and must be brought together for the
reaction to take place. This can be achieved by rapid mixing, phase-transfer catalysts, or
an emulsifying agent (the use of 1,4-Dioxane as a solvent is an example). The reaction
typically needs to be heated to initiate the process, however once started the Reimer-Tiemann
Reaction can be highly exothermic; this combination makes it prone to thermal runaways.
The formylation i.e. replacement of H by CHO group takes place at the ortho
position. If both ortho positions are filled, then the formylation occurs at para position.
Certain heterocyclic compounds too give such reaction as pyrroles and indoles. Sometimes
some abnormal products are also obtained alongwith the normal product aldehyde.
OH
CH3
CHCl3
OH
CHO
CH3
O
CH3CHCl3
4-Methyl-phenol 2-Hydroxy-5-methyl-benzaldehyde
4-Methyl-4-trichloromethyl-cyclohexa-2,5-dienone
3KOH+
Pyrrole
CHCl3
N
KN
H
CHON
Cl
OH-
1H-Pyrrole-2-carbaldehyde 3-Chloro-pyridine
Dichlorocarbenes can also react with alkenes and amines to form
dichlorocyclopropanes and isocyanides respectively. As such the Reimer-Tiemann reaction
may be unsuitable for substrates baring these functional groups.
Mechanism:
� Chloroform is deprotonated by strong base (Potassium hydroxide) to form
the chloroform carbanion which will quickly alpha-eliminate to give
dichlorocarbene which is the principle reactive species.
H ClCl
Cl
KOH ClCl
Cl
Cl
Cl_ :
chloroform carbanion dichlorocarbene
� Phenol also undergoes deprotonation. The hydroxide deprotonates the phenol
to give a negatively charged phenoxide ion. The negative charge is
delocalised into the aromatic ring, making it far more nucleophilic and
increases its ortho selectivity.
OH O O O O
Phenol Phenoxide ion delocalisation
_
_
_
� Nucleophilic attack of the dichlorocarbene from the ortho position gives an
intermediate dichloromethyl substituted phenol. After basic hydrolysis, the
desired product o-hydroxy benzaldehyde is formed.
O Cl
Cl
O ClCl
H
Cl
Cl
H
O
KOH
-KCl
Cl
O
H
O
H
H
OOH
: -
phenoxide o-hydroxy benzaldehydedichloromethyl substituted phenol
Synthetic applications:
1. Synthesis of 3-(3-formyl-4-hydroxy-phenyl)-2-tert-butyloxycarbonyl amino-
propionic acid
2. Synthesis of (±)-β-copaene
3. Synthesis of 2,6-diamino-pyridine-3-carbaldehyde
4. Synthesis of indatraline derivatives
5. Synthesis of (±)-trans-5-carboxytrimethylenoxyenterolactone
1.7 Clemmensen Reduction
Introduction: Clemmensen reduction is a chemical reaction described as a reduction of ketones
(or aldehydes) to alkanes using zinc amalgam and hydrochloric acid. This reaction is named
after Erik Christian Clemmensen, a Danish chemist. The most commonly used method for the
reduction of ketones to hydrocarbon (CH2 methylene group) by using zinc-mercury mixture
(Amalgum) in concentrated HCl acid is called Clemmensen reduction.
Statement:
Reduction of carbonyl groups of aldehydes and ketones to methylene groups with
zinc amalgam and hydrochloric acid:
General reaction:
Aryl alkyl ketones undergo reduction in presence of hydrochloric acid and zinc
amalgam, to saturated compound or alkane.
R1 R2
O HH
R1 R2
Zn(Hg)
H Cl
ketone hydrocarbon or alkane
Example: Acetophenone when treated with zinc amalgam in hydrochloric acid gives
ethyl benzene as a reduction product.
CH3
O
Zn(Hg) HCl CH2
CH3
Acetophenone ethyl benzene
Important features:
It is somewhat unusual reduction of carbonyl group because we expected an alcohol
by metal-acid reduction. The alcohol is stable for the Clemmensen reduction conditions,
hence mechanism of these reduction reaction proceeds throough an organo-zinc intermediates
but not through alcohol. This method is used for aromatic ketones which gives good yield.
The Clemmensen reduction is particularly effective at reducing aryl-
alkyl ketones, and not -COOH, -C=C-, -C≡C- groups. It is also not satisfactory for purely
aromatic ketones. Toluene is added to avoid the deposition of the product on zinc surface.
With aliphatic or cyclic ketones, zinc metal reduction is much more effective. The oxygen
atom is lost in the form of one molecule of water. The substrate must be stable in the strongly
acidic conditions of the Clemmensen reduction. Acid sensitive substrates should be reacted in
the Wolff-Kishner reduction, which utilizes strongly basic conditions.
Mechanism:
The reduction takes place at the surface of the zinc catalyst. The following proposal
indicates the formation of an intermediate 'zinc carbenoids'. Zinc abstracts the carbonyl
oxygen to form zinc oxide leaving the substrate in the form of a carbene which is deposited
on the zinc in the form of zinc carbenoid. This on abstraction of two protons from the acidic
medium, forms the product alkane.
OR
Ar
Zn
-ZnO
R
Ar
Zn ZnR
Ar
H+
Zn+
R
Ar
HH
+ R
Ar
H
H:
..: +
Ketone Alkanezinc carbenoid
Synthetic applications: 1. Synthesis of 3-alkyl-4-hydroxy-2(1H)-quinolinones
2. Synthesis of 3-alkyl-4-hydroxy-6-methylpyran-2-ones:
3. Synthesis of (–)-pumiliotoxin C
4. Synthesis of (5-methyl-2-propyl-octahydro-quinolin-1-yl)-phenyl-methanone
1.8 Pinacol –Pinacolone rearrangement
Introduction:
This reaction was first described by Wilhelm Rudolph Fittig in 1860. It is the
conversion that gave its name to this reaction, the acid-catalyzed elimination of water from
pinacol (tetramethylene ethylene glycol or 2,3-dimethyl 2,3-butan-di-ol) gives t-butyl methyl
ketone (2,2- dimethyl butan-3-one) which is commonly named as pinacolone. The pinacol
rearrangement or pinacol–pinacolone rearrangement is an acid catalysed conversion of a 1,2-
diol to a carbonyl compound. The name of the reaction comes from the rearrangement
of pinacol to pinacolone.
Statement:
Acid-catalyzed rearrangement of vicinal diols to aldehydes or ketones:
General reaction:
Pinacol as well as other 1,2-diols on reaction with an acid, acid chloride, zinc
chloride or other electrophilic reagents undergo a rearrangement of an alkyl group to yield
pinacolone or ketones or aldehyde is called Pinacol-Pinacolone rearrangement reaction.
Example: Pinacol in presence of acid like H2SO4, undergoes dehydration followed
by intramolecular rearrangement from 1,2 diol to a carbonyl compound pincacolone.
OHOH
CH3CH3 CH3CH3
aq. H2SO4
-H2O
OCH3
CH3 CH3 CH3
pinacol pinacolone
Important features:
Almost all diols can undergo such rearrangement reaction. If both the –OH groups
are not alike, then the one which yields a more stable carbocation participates in the reaction
to form the carbocation. The migration of alkyl groups in this reaction occurs such that the
group which stabilizes carbocation more effectively is migrated. This is in accordance with
their usual migratory aptitude, i.e. Aryl >>>> hydride > Phenyl> tertiary carbocation >
secondary carbocation > methyl cation. If two different diols are reacted, two different
carbonyl compounds are obtained as products, but crossed products are not obtained. This
indicates that the reaction is intramolecular one.
Mechanism:
Pinacol undergoes protonation in the aqueous acid and subsequently
loose water molecule to form a carbocation.
OHOH
CH3CH3 CH3 CH3
aq. H2SO4
-H2O
OH2+OH
CH3CH3 CH3 CH3
OH
CH3CH3 CH3 CH3
pinacol
-H2O +
Protonated pinacol carbocation
However subsequently, an alkyl group from the adjacent carbon migrates to the
carbocation center. This migration occurs because the oxonium ion is relatively more stable
than the carbocation.
OH
CH3CH3 CH3 CH3
OH
CH3CH3CH3
CH3O
CH3CH3CH3
CH3H+
carbocation
+
carbocation
+
oxonium ion
This oxonium ion then gets deprotonated and the carbonyl group is formed to give a
ketone Pinacolone.
O
CH3CH3CH3
CH3H -H+ O
CH3CH3CH3
CH3
+
oxonium ion pinacolone
Synthetic applications:
The reaction is used for synthesis of highly branched ketones. Cyclic ketones are
converted into pinacols which on rearrangement give spiro ketones.
1. Synthesis of (±)-furoscrobiculin B,
2. Synthesis of hydroxyphenstatin
3. Synthesis of (±)-fredericamycin A,
4. Synthesis of protomycinolide IV
5. Synthesis of 10,10-Diphenyl-10H-phenanthren-9-one
6. Synthesis of (2,3-Di-tert-butyldimethylsilyl-4-methoxy-phenyl)-(3,4,5-
trimethoxy-phenyl)-acetaldehyde
1.9 Benzilic acid rearrangement
Introduction:
The benzilic acid rearrangement is the rearrangement reaction of benzil with
potassium hydroxide to benzilic acid. This was first performed by Justus Liebig in 1838.
This reaction type is displayed by 1,2-diketones in general. The reaction product is an α-
hydroxy–carboxylic acid.
Statement:
Rearrangement of benzil to benzylic acid via aryl migration i.e. 1,2-diketones (α-
diketones) undergo a rearrangement in the presence of strong base (e.g., NaOH), to yield α-
hydroxycarboxylic acids. This process is called the benzilic acid rearrangement.
General reaction:
Base-induced rearrangement of benzil to benzylic acid via phenyl group migration.
More commonly perceived to include the migrations of other groups in α-dicarbonyl
compounds is known as Benzilic acid rearrangement.
Ar
O
Ar
OKOH
Ar
OH
OH
O
Ar
Benzil Benzilic acid
Example: 1,2-Diphenyl-ethane-1,2-dione, generally named as benzil undergoes
rearrangement reaction when heated with ethanolic or aqueous solution of potassium
hydroxide to give benzilic acid or hydroxyl diphenyl acetic acid salt of potassium.
k salt of
KOH
O
O H2 O/EtOHOH
1,2-Diphenyl-ethane-1,2-dione
100oC
Hydroxy-diphenyl-acetic acid
COO-K+
Important features:
The reaction takes place with both aliphatic and aromatic α-diketones and α-keto
aldehydes. Usually diaryl diketones undergo benzilic acid rearrangements in excellent yields,
but aliphatic α- diketones that have enolizable α-protons give low yields due to competing
aldol condensation reactions. Cyclic α- diketones undergo the synthetically useful ring-
contraction 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. Alkoxides that are readily
oxidized such as ethoxide (EtO-) or isopropoxide (Me2CHO-) are not synthetically useful,
since these species reduce the α-diketones to the corresponding α-hydroxy ketones. 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(s).
Mechanism:
The reaction is a representative of 1,2-rearrangements. These rearrangements usually
have migrating carbocations but this reaction is unusual because it involves a
migrating carbanion through a cyclic transition state.
A hydroxide anion attacks one of the ketone groups in 1,2-diketone in a nucleophilic
addition to form the hydroxyl anion.
O
O
PhPh
OH-
O
O
PhPhOH
O
OPhOH
Ph
_ _
hydroxyl aniondiketone
base
In the next step there occurs a bond rotation to conformer such that the migrating
group R is now in a position suitable for migration to the second carbonyl group which may
pass through a cyclic transition state with partial bonds as shown in fig. to form an alkoxide
ion.
O
OPhOH
Ph
O
O
Ph
OH
Ph
OH
OO
Ph Ph
__
alkoxide ioncyclic T.S.hydroxyl anion
Further the alkoxide ion abstracts proton from water and forms an α-hydroxy
carboxylic acid.
OH
OO
Ph Ph
H
OHH
OH
OOH
Ph Ph
H3O+
-H2 O
_
alkoxide ion
+
a-hydroxy carboxylic acid
Synthetic applications: 1. Synthesis of derivatives of steroids like cholesterol
2. Synthesis if 11-Hydroxy-11H-benzo[b]fluorene-11-carboxylic acid
3. Synthesis of carbohydrate moiety of (+)-K252a
4. Synthesis of novel 5-ring D-homosteroid
5. Synthesis of (±)-hinesol and (±)
1.10 Benzidine rearrangement
Introduction: Acid-catalyzed rearrangement of hydrazobenzenes to 4,4
hydrazobenzene contains a para substituent, then the favored product is p
aminodiphenylamine (Semidine rearrangement).
proceeds intramolecularly, is a classic
Statement:
Acid-catalyzed rearrangement of hydrazobenzenes to 4,4
known as Benzidine rearrangement.
General reaction: N,N’-diarylhydrazines generally referred as hydrazobenzene, undergoes
rearrangement intramolecularly
Important features:
If the hydrazobenzene contains a
aminodiphenylamine (Semidine rearrangement)
The benzidine rearrangement is claimed to be an example of the quite rare [5,5]
sigmatropic migration where the transition state involves ten atoms in a ring undergoing
rearrangement reaction. The formation of
[5,5] sigmatropic shift.
hinesol and (±)-agarospirol
1.10 Benzidine rearrangement
catalyzed rearrangement of hydrazobenzenes to 4,4′-diaminobiphenyls. If the
hydrazobenzene contains a para substituent, then the favored product is p
(Semidine rearrangement). The benzidine rearrangement
proceeds intramolecularly, is a classic mechanistic puzzle in organic chemistry.
catalyzed rearrangement of hydrazobenzenes to 4,4′-diaminobiphenyls
known as Benzidine rearrangement.
diarylhydrazines generally referred as hydrazobenzene, undergoes
molecularly to give 4,4'- diaminobiphenyl.
Important features:
If the hydrazobenzene contains a para substituent, then the favored product is
(Semidine rearrangement):
rearrangement is claimed to be an example of the quite rare [5,5]
where the transition state involves ten atoms in a ring undergoing
he formation of transition state seems to occur through a concerted
diaminobiphenyls. If the
hydrazobenzene contains a para substituent, then the favored product is p-
benzidine rearrangement, which
chemistry.
diaminobiphenyls is
diarylhydrazines generally referred as hydrazobenzene, undergoes
substituent, then the favored product is p-
rearrangement is claimed to be an example of the quite rare [5,5]
where the transition state involves ten atoms in a ring undergoing
seems to occur through a concerted
The rearrangement is normally promoted by acid and the active species is thought to
be diprotonated hydrazobenzene.
The rate determining step is the N-N cleavage /C-C bond formation. This is followed
by presumed rapid proton transfers.
Mechanism:
The hydrazobenzene absorb proton from the acidic medium and get diprotonated to
give a charged transition state involving ten atoms in all.
NH
NH
NH2NH2
+2H+
+ +
This dipositive ion undergoes electronic shift to form another dipositive ion.
NH2NH2
NH2H2N
+ +
+ +
This dipositive ion then restores the aromatic character by deprotonation.
NH2H2N NH2NH2
-2H++ +
Synthetic applications:
The synthetic application of Benzidine rearrangement may be limited because of the
many side products together with low yields. benzidine rearrangement of a constrained m-
nitrophenol derivative results in production of a cyclophane comprising a biphenyl group and
a polyether tether connected at the 4,4′ positions.
2. N,N‘-Diaryl hydrazides tethered with a polyether group at the meta positions
undergo [5,5]-sigmatropic (benzidine) rearrangement reactions to furnish 4,4‘-diamino-
biphenyls (benzidines) strapped with a polyether unit at the 2,2‘-positions.
3. N,N‘-Aryl hydrazides with substituents at the ortho or meta positions undergo
highly regioselective [5,5]-sigmatropic rearrangement reactions to furnish benzidines in good
to excellent isolated yields. The presence of single substituent at either the ortho or meta
position provides sufficient bias, effectively suppressing the formation of diphenylene, the
major byproduct of the conventional benzidine rearrangement reaction.
1.11 Cannizzaro reaction
Introduction:
The Cannizzaro reaction, named after its discoverer Stanislao Cannizzaro, is
a chemical reaction that involves the base-induced disproportionation of an aldehyde lacking
a hydrogen atom in the alpha position. Cannizzaro first accomplished this transformation in
1853, when he obtained benzyl alcohol and potassium benzoate from the treatment of
benzaldehyde with potash (potassium carbonate).
Statement:
Base-catalyzed disproportionation reaction of aromatic or aliphatic aldehydes
with no α-hydrogen to corresponding acid and alcohol. If the aldehydes are different, the
reaction is called the “crossed Cannizarro reaction”:
General reaction:
An aliphatic or aromatic aldehyde with no α-hydrogen when treated with
concentrated solution of alkali such as NaOH or other strong bases, undergoes an oxidation-
reduction reaction to produce an alcohol and the salt of a carboxylic acid. This reaction is
known as Cannizzaro reaction.
Example:
Benzaldehyde which doesnot have α-hydrogen when treated with concentrated
solution of alkali such as NaOH, give benzyl alcohol and Na salt of benzoic acid.
CHONaOH
CH2OH COONa
2 +
benzaldehyde benzyl alcohol Na salt of benzoic acid
Important features:
More typically, the reaction would be conducted with sodium or potassium
hydroxide. For aldehydes with a α-hydrogen atom, i.e. R2CHCHO, Aldol condensation is
preferred. Cannizzaro reaction is an example of a reaction which involves Hydride shift.
[Hydride is hydrogen with the bonding pair of electrons hence a negative charge]
When Cannizzaro reaction is carried out in D2O, the alcohol formed doesnot contain
C-D bond, indicating the direct transfer of hydride ion from one aldehyde molecule to
another molecule occurs.
There are certain carbonyl compounds such as 1,2-dialdehydes, α-keto aldehydes
can undergo intramolecular Cannizzaro reaction because they are capable of transferring a
hydride ion within the molecule. When two different aldehydes are used, a crossed
Cannizzaro reaction can also be seen.
Cannizzaro reaction fails when there is a steric hindrance. Eg. Di-o-substituted
benzaldehyde doesnot undergo Cannizzaro reaction.
Mechanism:
� Step I: The reaction begins with nucleophilic attack of hydroxide on the carbonyl
center of one aldehyde molecule to form an oxyanion.
H
O
PhOH Ph
O
OH
H
C+ :.
. _
_
aldehyde oxyanion
� Step II: The resulting anion attacks another molecule of aldehyde, transferring hydride
in an intermolecular hydride ion transfer directly from one aldehyde to another
aldehyde resulting into the carboxylic acid and an alkoxide ion.
Ph
O
OH
H
C
O
HPhPh
O
OHC Ph
O
H
H
C+
_
+
_
oxyanion aldehyde carboxylic acid alkoxide ion
� Step III: In the final step of the reaction, in the acid-base reactions of carboxylic acid
and an alkoxide ion formed exchange a proton. In the presence of a very high
concentration of base.
H
O
OHCNaOH H
O
ONaC+ + H2O
H
O
H
H
C H
OH
H
H
C OH-
_
H2O+ +
Synthetic applications: 1. Synthesis of naphthalen-1-yl-methanol
2. Synthesis of N-Cyclohexyl-benzamide
3. Synthesis of dibenzoheptalene bislactones
4. Synthesis of 4-chloro-3-(hydroxymethyl) pyridine
5. Synthesis of (+)-isokotanin
Summary: [Points to remember]:
Reaction Substrate Reagents
/Reaction
Conditions
Product
1. Claisen conden. ester containing an α-
hydrogen
sodium alkoxide β-keto esters
2. Perkin reaction aromatic aldehydes
and acid anhydrides
alkali salt of the acid α,β-unsaturated
carboxylic acids
3. Mannich Reaction Aryl alkyl ketone formaldehyde and
secondary amine
β-amino ketone
4. Knoevengel
Condensation
aldehyde or a ketone compound having an
active methylene
group & a base
unsaturated
compound
5. Reformatsky
Reaction
aldehydes or ketones zinc & α-halo esters β-hydroxy esters
6. Reimer-Tiemann
Reaction
phenols chloroform
and alkali
phenolic aldehydes
7. Clemmensen
Reduction
aldehydes and
ketones
hydrochloric acid
and zinc
Saturated compound
/alkane
8. Pinacol –
Pinacolone
rearrangement
vicinal diols acid, acid chloride,
zinc chloride or other
electrophilic reagents
aldehydes or ketones
9. Benzilic acid
rearrangement
1,2-Diketones (α-
diketones)
strong base
(e.g., NaOH),
α-hydroxy
carboxylic acids
10. Benzidine
rearrangement
N,N’-
diarylhydrazines
Acid 4,4'- diamino
biphenyl
11. Cannizzaro
reaction
of aromatic or
aliphatic aldehydes
with no α-hydrogen
Base acid and alcohol
Abbreviations used in the topic (as per the sequence in which they appear)
M Na/K/Li LDA lithium diisopropylamide
THF tetrahydrofuran
HMPA hexamethylphosphoric acid
triamide (hexamethylphosphoramide)
CSA camphorsufonic acid
TFA trifluoroacetic acid
DCM dichloromethane
PMP 4-Methoxy-phenylamino
DMSO dimethylsulfoxide
CBz benzyloxycarbonyl
EDDA ethylenediamine diacetate
PMB p-methoxybenzyl
Boc t-butoxycarbonyl
TMS trimethylsilyl
OTBDMS tert-butyloxycarbonyl-4- tert-butyldimethylsilyl
Bn benzyl
Ts p-toluenesulfonyl
TBDMS t-butyldimethylsilyl
BOM benzyloxymethyl
DBAL-H diisobutylaluminum hydride
CTAP cetyl trimethylammonium
permanganate
LDA lithium diisopropylamide
DMF N,N-dimethylformamide
DCC dicyclohexylcarbodiimide
DMAP N,N-4-dimethylaminopyridine
CBS Corey-Bakshi-Shibata reagent
Exercises
[A] OBJECTIVE TYPE QUESTIONS
A] Select the most correct alternative from among those given below.
1. Base-catalyzed condensation of an ester containing an α-hydrogen atom with a molecule
of the same ester or a different one to give β-keto esters is known as ……… .
a) Claisen condensation b) Knoevenagel condensation c) Mannich Reaction d)
Reformatsky Reaction
2. In a Claisen condensation, molecule of ethyl acetate condenses with other molecule of
ethyl acetate in the presence of sodium ethoxide to form ……………….
a) acetic acid b) ethyl acetoacetate c) sodium acetate d) ethanol
3. Aromatic aldehyde reacts with aliphatic acid anhydride in presence of the sodium salt of
the aliphatic acid to give………… in Perkin reaction.
a) acid unhydride b) carboxylic acid c) α -β unsaturated acid d) hydroxy acid
4. Benzaldehyde when treated with acetic anhydride in presence of ……………gives α -β
unsaturated acid cinnamic acid in Perkin reaction.
a)ethyl acetate b)sodium ethoxide c) ethyl acetoacetate d) sodium acetate
5. In Perkin reaction, acetic anhydride produce………….intermediate in the first step.
a) oxonium ion b)carbene c) carbanion ion d)carbonium ion
6. The condensation of aldehyde or ketone with formaldehyde and ammonia or a primary or
secondary amine forming a β-aminocarbonyl compound is known as
……………reaction
a) Reformatsky Reaction b) Mannich c) Claisen condensation d) Perkin reaction
7. There is formation of an …………. ion from the amine and the formaldehyde in the first
step of Mannich reaction
a) ammonium b)carbanion c)carbonium d) iminium
8. In Mannich reaction acetophenone is deprotonated to get the…………..ion.
a) ammonium b)carbanion c)carbonium d) iminium
9. condensation reaction between an aldehyde or a ketone with a compound having an active
methylene group in presence of a base to yield an unsaturated compound is called
…………..reaction.
a) Knoevenagel b) Perkin c)Claisen d) Cannizzaro
10. Condensation of aldehydes or ketones with organozinc derivatives of α-halo esters to
yield β-hydroxy esters: is called ……………reaction.
a) Reformatsky b) Knoevenagel c)Claisen d) Cannizzaro
11. The formylation of the phenol in basic condition with …………………to produce an
aromatic aldehyde is called Reimer-Tiemann Reaction
a) Carbon tetrachloride b) chloroform c) chlorine d) alpha chloro ester
12. Clemmensenreduction is a chemical reaction described as a reduction of ketones
(or aldehydes) to …………. using zinc amalgam and hydrochloric acid.
a) alkanes b) secondary alcohol c)primary alcohol d) carboxylic acid
13. In the following reaction product A is…………
CH3
O
Zn(Hg) HClA
Acetophenone
a) methyl benzene b) ethyl benzene c) phenol d)benzoic acid
14. Acid-catalyzed rearrangement of vicinal diols to aldehydes or ketones is ……..reaction.
a) Pinacol –Pinacolone rearrangement b) Benzidine rearrangement c)Reimer Tiemanns
d) Mannich
15. In the following reaction product A is…………
Ar
O
Ar
OKOH
A
diketone
a) diol b) benzoic acid c)benzilic acid d) benzidine
16. 1,2-diketones (α-diketones) undergo a rearrangement in the presence of strong base (e.g.,
NaOH), to yield α-hydroxycarboxylic acids. This process is called the
………….rearrangement
a) Pinacol –Pinacolone b) benzilic acid c) Claisen d) Benzidine
17. Acid-catalyzed rearrangement of hydrazobenzenes to 4,4′-diaminobiphenyls is known as
……………….rearrangement.
a) Benzidine b) Pincaol-Pinacolone c) Benzilic acid d) Claisen
18. Base-catalyzed disproportionation reaction of aromatic or aliphatic aldehydes with no α-
hydrogen to corresponding acid and alcohol is called …………… reaction.
a) Benzidine b) Cannizzaro c) Claisen d) Perkin
19. The product B in the given reaction is …………………...
CHONaOH
CH2OH
B2 +
benzaldehyde benzyl alcohol .
a) Sodium Benzoate b) Benzoic acid c) phenol d) ethyl benzene
20. In the following reaction the substrate A is………………..
CHCl3
OH
CHO
A3KOH
o-hydroxy benzaldehyde
a) benzaldehyde b) acetophenone c) phenol d) benzene
Answer:
1. a) Claisen 2 acid b) ethyl acetoacetate 3. c) α -β unsaturated acid 4. d) sodium
acetate 5 c) carbanion ion 6. b) Mannich 7. d) iminium 8. b)carbanion 9. a)
Knoevenagel 10 . a) Reformatsky 11 b) chloroform 12. a) alkanes 13. b) ethyl
benzene 14. a) Pinacol –Pinacolone rearrangement 15. c)benzilic acid 16 b) benzilic
acid 17. a) Benzidine 18. b) Cannizzaro.
19. a) Sodium Benzoate 20. c) phenol
[B] LONG AND SHORT ANSWER TYPE QUESTIONS:
1. What are name reactions?
2. Discuss the mechanism of the following reactions with suitable example.
OR
3. Write any two synthetic applications of the following.
1. Claisen condensation.
2. Perkin reaction
3. Mannich Reaction
4. Knoevengel Condensation
5. Reformatsky Reaction
6. Reimer-Tiemann Reaction
7. Clemmensen Reduction
8. Pinacol –Pinacolone rearrangement
9. Benzilic acid rearrangement
10. Benzidine rearrangement
11. Cannizzaro reaction
