Some Reaction Mechanisms

1. Baeyer-Villiger oxidation.
2. Cannizzaro reaction.
3. Perkin reaction.
4. Diels Alder reaction.
5. Arndt-Eistert Reaction/Synthesis.
6. Mannich reaction.

1
Definition: “The Baeyer-Villiger oxidation is an organic reaction used to
convert a ketone to an ester or a lactone from a cyclic ketone, using
peroxyacids or peroxides as the oxidant.”

Named After: The reaction is named after Adolf von Baeyer and Victor Villiger
who first reported the reaction in 1899.

General Equation:

2
Oxidizing Agents Used:
Baeyer-Villiger oxidations can be accomplished using a wide range of oxidizing
agents like hydrogen peroxide (H2O2), 3-chloroperbenzoic acid (m-
chloroperoxybenzoic acid), peroxyacetic acid & peroxytrifluoroacetic acid etc.

For Your Concept:

• Peroxytrifluoroacetic acid is the most reactive

of the peracids, probably because the
trifluoroacetate ion is verygood leaving
group.

3
Examples:
[1]. When acetophenone reacts with a peroxy acid, phenyle acetate is formed.

[2]. Similarly when the cyclohexanone reacts with 3-chloroperbenzoic acid, 6-

hexanolactone (a cyclic ester) is formed.

4
Stepwise Mechanism of Baeyer-Villiger Oxidation

5
6
Retention of stereochemistry by the migrating group:
• Migration is concerted (simultaneous) with the departure of the leaving
group. This concerted step is rate determining.

• When the two ligands on the carbonyl carbon in the ketone are different i.e.
in unsymmetrical ketones, Baeyer-Villiger oxidation is regioselective. Of
the two alpha carbons in the ketone, the one that can stabilize a positive
charge more effectively, which is the more highly substituted one, migrates
from carbon to oxygen preferentially.

Migratory Aptitude: It is the relative ability of a migrating group to migrate in a

rearrangement reaction. Migrating groups with greater electron donating
power have correspondingly greater migratory aptitude because of the
increased ability to stabilize a positive charge in the transition state. This can
be affected by the leaving group (whichever gives a more stable carbocation).

Order of Migratory Aptitude: -H > ph > ter alkyl > sec alkyl > pri alkyl > methyl
7
Applications:

1. Baeyer-Villiger oxidation is widely used for synthesizing lactones from

cyclic ketones.

2. Baeyer-Villiger reaction is widely appreciated in organic synthesis as it is

applicable to a broad range of carbonylic compounds while the moiety
that will migrate during the reaction can also be predicted to some extent.

3. In Baeyer-Villiger reaction, the migrating group will typically retain its

configuaration. This allows effective and selective oxidation reactions.

Drawback of Baeyer-Villiger Oxidation:

• A major drawback of the reaction is the intrinsic need for a potent and
therefore hazardous oxidising agent.

8
Definition: “The disproportionation redox reaction of a non-enolizable
aldehyde (without α-hydrogen) in presence of a strong base to furnish an
alcohol and a carboxylic acid is called Cannizzaro reaction.”
OR
• “The Cannizzaro reaction is a redox reaction in which two molecules of an
aldehyde are reacted to produce a primary alcohol and a carboxylic acid
using a hydroxide base.”

• In this reaction, one molecule of aldehyde is reduced to the

corresponding alcohol, while a second one is oxidized to the carboxylic
acid.
• First Discovered By: Cannizaro reaction was first discovered by an Italian
Chemist Stanislao Cannizaro (1826-1910).

• Alternate Names: It is also named as self oxidation-reduction,

disproportion, basic hydrolysis, nucleophilic addition reactions.
9
General Equation:

Important Note:
In case of aldehydes that do have the a-hydrogen, Aldol condensation reaction
takes place preferentially.

Example No. 1:
Formaldehyde is disproportionated to formic acid and methyl alcohol in strong
alkali.

10
Example No. 2: Benzaldehyde can be converted into benzoic acid and benzyl
alcohol as follows:

For your concept

Definition of an Alkali: An alkali can be defined as a base that dissolves

in water. A solution of a soluble base has a pH greater than 7.
Definition of a Base:
1. According to Arrhenius: Bases are substances which produce hydroxide
ions in solution.
2. According to Bronsted-Lowry Theory: A base is a proton (hydrogen ion)
acceptor.
3. According to lewis theory: A base is an electron pair donor. 11
• Another Definition: “Aldehydes with no α-hydrogen when treated with
concentrated alkali or other strong bases undergo self oxidation and
reduction to produce an alcohol and the salt of a carboxylic acid. This
disproportionation reaction is also known as a Cannizzaro's reaction.”

• Thus, aromatic aldehydes, formaldehydes, trialkyl acetaldehyde,

heterocyclic aldehydes undergo Cannizaro reaction.

• Examples:

12
 For Your Concept
Disproportionation Reaction: “Disproportionation is a chemical reaction,
typically a redox reaction, where a molecule is transformed into two or more
dissimilar products.” OR
• “A disproportionation reaction is when one entity undergoes both oxidation
as well as reduction simultaneously in the same reaction and two different
products are formed.”

• Disproportionation reactions follow the form: 2A → A' + A”.

• Example: Phosphorus disproportionates to phosphine and hypophosphite

in alkaline medium. In this case, one P atom is reduced to -3 oxidation
number (in PH3) and three P atoms get oxidized to +1 (in NaH2PO2).

13
 Mechanism of Cannizzaro Reaction
• Step 1 and 2: The cannizzaro reaction is initiated by the nucleophilic attack
of a hydroxide ion to the carbonyl carbon of an aldehyde molecule by
giving a hydrate anion (unstable intermediate).

• This hydrate anion can be deprotonated to give a dianion (unstable

intermediate) in a strongly alkaline medium. In this second step, the
hydroxide behaves as a base (as per Bronsted-Lowry Theory).

• Step 3: Now a hydride ion, H- is transferred either from the monoanionic

species (case-1) or dianionic species (case-2) onto the carbonyl carbon of
another aldehyde molecule.
14
• In this process the dianion converts to a carboxylate anion and the
aldehyde to an alkoxide.

• The strong electron donating effect of O- groups facilitates the hydride

transfer and drives the reaction further. This is the rate determining step of
the reaction. 15
Step 4:
• The alkoxide then picks up a proton from water to provide the alcohol
final product, while the caboxylate is converted to the carboxylic acid
product after acid work-up.

16
Limitations of Cannizzaro Reaction:
1. The applicability of Cannizzaro reaction in organic synthesis is limited as
the yield is not more than 50% for either acid or alcohol formed.

2. Cannizzaro reaction is limited to non-enolizable aldehydes (such as

formaldehyde) which has no α-hydrogen (on the carbon next to the –CHO
group).

Crossed Cannizzaro Reaction:

• “When a mixture of formaldehyde and a non enolizable aldehyde is
treated with a strong base, the later is preferentially reduced to alcohol
while formaldehyde is oxidized to formic acid. This variant is known
as crossed Cannizzaro reaction.”
17
Note: When the aldehydes are not identical, this is referred to as a crossed
Cannizzaro reaction.

Example: Benzyl alcohol and formic acid are obtained when a mixture of
benzaldehyde and formaldehyde is treated with alkali.

• The reason may be: The initial nucleophilic addition of hydroxide anion is
faster on formaldehyde as there are no electron donating groups on it.

• The preferential oxidation of formaldehyde in crossed Cannizzaro reactions

may be utilized in the quantitative reduction of some aldehydes.

18
 [3]. Perkin Reaction (Perkin Condensation)
Definition: “The Perkin reaction is a reaction for making an α-β unsaturated
aromatic acid (cinnamic acid) by heating an aromatic aldehyde with an acid
anhydride (acetic anhydride) in the presence of a base (sodium acetate or
potassium carbonate).”
OR
• “The Perkin reaction is an organic reaction that is used to make α,β-
unsaturated aromatic acids (cinnamic acids) by the condensation of an
aromatic aldehyde and an acid anhydride, in the presence of an alkali salt of
the acid.”

Named After: The Perkin reaction is developed by English chemist William

Henry Perkin in the 19th century.

Catalyst Used: In this reaction catalyst used mostly is sodium salt of an acid
and the acid is same as present in the acid anhydride. For example: In the case
of acetic anhydride, sodium acetate is used. In the case of propionic
anhydride, sodium propionate is used. 19
General Equation: The general equation of Perkin Reaction is given as:

• NaOAc = Sodium Acetate.

Example No. 1: When benzaldehyde reacts with propionic anhydride in the

presence of sodium propionate, α-methylcinnamic acid is formed:

20
Example No. 2: When benzaldehyde reacts with acetic anhydride in the
presence of sodium salt of acetic acid, cinnamic acid is produced along with
acetic acid.

OR

21
 Mechanism of Perkin Reaction
Step 1: Formation of anion of anhydride: The acetate ion of sodium acetate
attracts the proton of anhydride and anion of anhydride is formed along with
acetic acid.

Step 2: Nucleophilic Addition: Addition of anion of anhydride to the carbonyl

carbon of aromatic aldehyde take place to form an adduct.

22
Step 3: Protonation: Acetic acid (formed in the first step) donates a proton to
the adduct formed in second step to form an intermediate product -1.

Step 4: Internal proton transfer and elimination of water: Internal proton

transfer & elimination of water take place forming an intermediate product -2.

Note: For the elimination of water, temperature of about 170-180oC is

maintained. 23
Step 5: Hydrolytic Cleavage: Hydrolytic cleavage of intermediate product-2
takes place leading to the formation of Cinnamic acid and Acetic acid.

intermediate product -2

Important conditions for Perkin Condensation:

1. The aldehyde used in this reaction must be Aromatic. Because if aliphatic
aldehydes are used, than Aldol condensation will take place rather than
Perkin condensation and the product will be an Aldol not α-β unsaturated
carboxylic acid.
2. This reaction only takes place in the presence of a base.
3. In step 4, for the removal of water molecule, 170-180oC temperature
must be maintained.

24
Applications of Perkin reaction: The applications of Perkin reaction are:
1. Many pharmaceutical companies use cinnamic acid in the manufacturing
of certain topical drugs e.g. Peru balsam (used for the treatment of
topical wounds and infections and as a flavoring in the food industry.),
2. Shea Butter: Cinnamic acid is used in the manufacturing Shea Butter has
such a large healing fraction, in addition to moisturizing fraction, regular
use of this natural cream can treat many skin problems, including
blemishes, wrinkles, itching, sunburns, small skin wounds, eczema, skin
allergies, insect bites, frost bite, and other skin conditions.
3. The result of the Perkin reaction, cinnamic acid, is an important element of
the modern perfume industry.
4. Dye manufacturers also use cinnamic acid in the synthesis of indigo dye.
5. Cinnamic acid derivatives is used in the preparation of anti-cancer agents
e.g. Ferulic acid etc.

25
 [4]. Diels-Alder Reaction
Definition: “The cycloaddition reaction between a conjugated diene (a
molecule with two alternating double bonds) and a dienophile (alkene or
alkyne) to form unsaturated six-membered rings (an adduct) is known as Diels-
Alder reaction.”

Named After: This reaction is named after two German scientists Otto Diels &
Kurt Alder who received Noble prize in chemistry in 1950 for discovering it.

General equation: The general equation of Diels-Alder reaction is given as:

26
• In conventional terminology, this is a 1,4-addition of a diene and a
dienophile.
Net Result: The three double bonds in the two starting materials are
converted into two new single bonds and one new double bond.

Important Consideration: Typically, the Diels-Alder reaction works best when

either the diene is substituted with electron donating groups (like -OR, -NR2,
etc) or when the dienophile (alkene or alkyne) is substituted with electron-
withdrawing groups (like -NO2, -CN, -COR, etc).

Example No. 1: When 1,3-butadiene reacts with Methyl acrylate in the

presence of AlCl3 at 20oC to form 1-Carbomethoxy-3-cyclohexene.

27
Example No. 2: When 1,3-butadiene reacts with acrolein at 100oC, 3-
Cyclohexene-1-carboxaldehyde is formed:

Example No. 3: Reaction of 1,3-butadiene with ethyne to form 1,4-

cyclohexadiene.

Note: Although heat is not required in Diels-Alder reactions, heating up the

reaction will improve yield. 28
 For your concept
Adduct: An adduct is a product of a direct addition of two or more molecules,
resulting in a single reaction product containing all atoms of all components.
The resultant is considered a distinct molecular species. Example:

Conjugated Diene: Conjugated dienes have conjugated double bonds

separated by one single bond.

Dienophile: Dienophile are diene loving and readily reacts with a diene in the
Diels-Alder reaction. 29
Mechanism of Diels-Alder reaction:
• The mechanism of this reaction is concerted meaning that all the bond
forming and bond-breaking happens at the same time.
• The reaction proceeds in a 1-step cycloaddition. No intermediates are
formed in this reaction.

Note: If the arrows are drawn in the reverse direction, the result would be
same.

Conformational requirements for Diels-Alder reaction:

• One property of the Diels-Alder reaction is that the diene is required to be
in the s-cis conformation for the Diels-Alder reaction to work. 30
• In solution, the carbon-carbon single bond in the diene that connects the
two alkenes is constantly rotating, so at equilibrium there is usually some
mixture of dienes in the s-trans conformation and some in the s-cis
conformation.

• The diene that are at that moment in the s-trans conformation do not react,
while the diene in the s-cis conformation can easily react. Similarly, an s-cis
diene in ring form can readily react due to being locked up in one
stererochemical form.

Stereochemistry of Diels-Alder reaction:

• If a dienophile (alkenes or alkynes) is disubstituted, there is the possibility
of different stereochemistry in the products. 31
• In Diels-Alder reaction, stereochemistry of the reactants is retained in the
products. If the stereo-confirmation of dienophile is s-cis, than the product
will have s-cis stereo-confirmation and vice versa.

Important Conditions Of Diels-Alder Reactions:

1. The diene present must be conjugated.
2. There should be electron-withdrawing groups attached to the dienophile
i.e. CHO, COR, COOR, CN, C=C, Ph or halogen.
3. The diene must be in s-cis confirmation. 32
Applications of Diels-Alder reaction:

1. Diels-Alder reaction is responsible for the synthesis of the steroids i.e.

cortisone and cholesterol.

2. This reaction is also responsible for the preparation of hydrogels for drug
delivery system.

3. Diels–Alder reaction also synthesize Prephenate, a biosynthetic precursor

of the amino acids i.e. phenylalanine and tyrosine.

4. Solanapyrone A is being synthesized by Diels-Alder reaction. The drug is an

anti-cancer medication.

5. Salvinorin A is also being synthesized by this reaction. The compound has

potential uses in psychotherapeutic treatment and Alzheimer's
treatment.
33
 For your concept
Why the dienes must be in s-cis conformation? The s-cis conformation is
higher in energy, less stable and more reactive than the s-trans conformation,
due to steric hindrance. That’s why the diene molecule must adopt s-cis
conformation.
Acrolein: Acrolein is the simplest unsaturated aldehyde.

Methyl Acrylate: It is the methyl ester of acrylic acid. Acrylic acid is the
simplest unsaturated carboxylic acid, consisting of a vinyl group connected
directly to a carboxylic acid.

Psychotherapeutic Treatments: During psychotherapy, a person with

depression talks to a licensed and trained mental health care professional who
helps him or her identify and work through the factors that may be causing
them to become depressed. 34
Alzheimer Diseases: Progressive mental deterioration that can occur in middle
or old age, due to generalized degeneration of the brain which causes
dementia.

Prephenate: Prephenic acid, commonly also known by its anionic form

prephenate, is an intermediate in the biosynthesis of the aromatic amino acids
phenylalanine and tyrosine.

What is meant by s in s-cis and s-trans?

• The s stands for single, as in single bond. It means the double bonds are cis
or trans to each other based around the single bond.

35
 [5]. Arndt-Eistert Reaction
Definition: “The extension of carboxylic acid by one methylene (-CH2-) unit
through the reaction of acyl chloride (acid chloride) with diazomethane is
referred to as the Arndt–Eistert reaction or synthesis.”
OR
• The Arndt–Eistert reaction or Arndt–Eistert synthesis is a series of chemical
reactions designed to convert a carboxylic acid to a higher carboxylic acid
homologue (i.e. contains one additional carbon atom) and is considered a
homologation process.”
OR
• “Arndt-Eistert Synthesis is an understandable method for changing an acid
into its next higher analogue or to a derivative of the homologous acid,
such as an amide or ester.”

Named After:
• Named for the German chemists Fritz Arndt (1885–1969) and Bernd Eistert
(1902–1978). 36
• General Reaction Equation:

• Description: Classic Arndt–Eistert synthesis uses thionyl chloride to convert

the starting acid to an acid chloride (or any procedure can be used that will
generate an acid chloride). Acid chlorides react with diazomethane to give
diazoketones. In the presence of a nucleophile (water) and a metal
catalyst (AgO), diazoketones will form the desired acid homologue.

• Note: Diazoketones are typically generated as described here, but other

methods such as diazo-group transfer can also apply.
• Since diazomethane is toxic and violently explosive, many safer
alternatives have been developed, such as diazo(trimethylsilyl)methane. 37
 For Your Concept
• Homologation Reaction: A homologation reaction is any chemical reaction
that converts the reactant into the next member of the homologous series.

• A homologous series is a group of compounds that differ by a constant unit,

generally a (-CH2) group. The reactants undergo a homologation when the
number of a repeated structural unit in the molecules is increased.
• The most common homologation reactions increase the number of
methylene (-CH2) units in saturated chain within the molecule.

Structure of Diazo (trimethylsilyl) methane

38
• Example: Conversion of 4-nitrobenzoic acid to 4-nitrophenyl acetic acid.

4-Nitrobenzoic acid 4-nitrophenyl

diazomethyl ketone
chloride

Arndt-Eistert Reaction Mechanism (Summarized Form)

• The carboxylic acid is converted to acid chloride which then reacts with
(acetylates) diazomethane to form diazoketone.

• Nitrogen is removed from diazketone so that unstable intermediate

carbene is formed which further undergo rearrangement to form a ketene.
39
• Ketene reacts with water molecule to form acid. Ketene may also reacts
with ammonia to form amide and alcohol to form ester.

40
 Mechanism of Action in Detail
• It can be explained in the following steps:

• Step – 1: In the first step of an Arndt-Eistert Homologation reaction, a

carboxylic acid is activated by chlorinating it with thionyl chloride (SOCl2)
and converting it into an acid chloride (“acyl chloride”).

• Step – 2: In the second step, acid chloride formed in the previous step is
treated with diazomethane. It results in the formation of a diazoketone.
• Note: Excess diazomethane can be destroyed by addition of small amounts
of acetic acid or vigorous stirring. 41
• Step – 3: In this step, the diazoketone is decomposed in the presence of a
silver catalyst (usually AgO2 or AgNO3) together with heat (25 - 750°C) or
light energy resulting in a carbene.

• Step – 4: Carbene then undergoes a 1,2-rearrangement (Wolff

Rearrangement) to form ketene which quickly reacts with any nucleophile
that may be present in solution. Nucleophiles may be water (to yield
carboxylic acid), alcohols (to give esters), or amines (to give amides).
Tautomomerism finally plays a role in getting the product. 42
Step - 4

43
Note: In Exams it is better to write step wise mechanism. Don’t repeat it twice.

Applications:
1. This reaction has application in synthesis of unsaturated diazoketone and
amino acids.

2. This reaction is used to prepare the higher analogues of carboxylic acids

and their derivatives.

3. Arndt–Eistert synthesis is a popular method of producing β-amino acids

from α-amino acids and gamma-amino acids from β-amino acids.

44
 [6]. Mannich Reaction
Definition: “The Mannich reaction is an organic aminoalkylation reaction used
to convert ammonia or a primary or secondary amine and two carbonyl
compounds (one non-enolizable and one enolizable) to a β-amino carbonyl
compound, also known as a Mannich base, using an acid or base catalyst.”
OR
• “Mannich reaction is the multi-component condensation of a
nonenolizable aldehyde (usually formaldehyde), ammonia or a primary or
secondary amine and an enolizable carbonyl compound (containing at least
one alpha hydrogen atom) to give aminoalkylated products.”
General Equation:

45
Named After:
• Mannich reaction was named after a German Chemist Carl Mannich in
1912.

Important Facts:

1. In the Mannich reaction, primary or secondary aliphatic amines or

ammonia, are employed for the activation of formaldehyde. Mostly
dimethyl amine is used. Tertiary amines do not have an α-hydrogen.

2. The aromatic amines do not undergo Mannich reaction.

3. Instead of formaldehyde, other aliphatic or aromatic non-enolizable

aldehydes or ketones can be employed.

4. This reaction is acid catalyzed and is usually carried out in aqueous or

alcoholic solution at room temperature.
46
Example 1: Acetone reacts with dimethyl amine and formaldehyde in the
presence of acid to form 4-dimethylaminobutan-2-one which is Mannich base.

Example 2: Acetophenone reacts with formaldehyde and diethylamine in the

presence of acid to form 3-(Diethylamino)-1-phenylpropan-1-one.

47
Mechanism of Mannich Reaction:
• The Mannich reaction is an example of nucleophilic addition reaction and
comprises of following three phases.

Phase-1: Formation of Iminium ion:

• In this step, a lone pair of nitrogen of the amine attacks carbonyl carbon of
the formaldehyde.

• Then, deprotonation of nitrogen removes the positive charge, and

protonation of oxygen remove the negative charge and the neutral
intermediate is obtained.

• Further protonation of hydroxyl group yields a better leaving group which

is expelled in the next step as water.

• And a resonance-stabilized iminium ion (Schiff base) is obtained.

48
Phase-2: Enolization of the Enolizable Carbonyl Compound:
• Since the reaction is carried out in acidic conditions, the enolizable
carbonyl compound is converted (tautomerized) to enol form because
oxygen of keto form is protonated and α hydrogen is removed.
49
Phase 3: Formation of the Mannich Base:
• The enol intermediate then attacks the iminium ion at positively charged
carbon adjacent to nitrogen and at the same time gets
deprotonated, finally producing a β-aminocarbonyl compound
(Mannich base).

50
Applications of Mannich reaction:
1. β-aminocarbonyl compounds can be conveniently reduced to β-
aminoalcohols, which show considerable pharmacological activity.

2. Mannich reaction is used in the synthesis of alkyl amines, peptides,

nucleotides, antibiotics, alkaloids and polymers.

3. It is also used in the synthesis of Pharmaceutical drugs e.g. fluoxetine

(antidepressant), tramadol and tolmetin (anti-inflammatory drug).

4. It is also used in the manufacturing of soap and detergents.

5. By the thermal degradation of Mannich bases, α, β-unsaturated ketones

can be formed.

6. The synthesis of tropinone (a precursor of atropine) and related

compounds is done by a Mannich reaction.
51
7. The involvement of the Mannich Reaction has been proposed in many
biosynthetic pathways, especially for alkaloids.

Limitations:
1. Range of application is limited (e.g. confined to amino methylation).

2. In many cases undesired side products are formed.

3. The ability to control regio- and stereoselectivity is generally

unsatisfactory.

52
 For your concept
Imine: An imine is a functional group or chemical compound containing a
carbon–nitrogen double bond.

Alkaloids: Any of a class of nitrogenous basic organic compounds of plant

origin that have pronounced physiological/pharmacological actions on
humans. They include many drugs and poisons.

53
54