SYNTHETIC ORGANIC

CHEMISTRY

DINESH – 2020311011
SRIVATHSHKALEESHWARAN – 2020311045
ARUNACHALAM - 2020311007
INTRODUCTION:

Synthetic Organic Chemistry is related to the chemical

science involving in the construction of specific chemical
compounds from simple compounds. In synthetic organic
chemistry the synthesis is implied to the aspect of a planned
sequent route resulting in products with desired activity. The
process permits synthesis of naturally occurring compounds
with actual structure or once needed with structural
variation to enhance desired characteristics. Synthetic
Organic Chemistry journals emphasis the fields of Organic
Chemistry. Here we talk about the synthesis of organic
compounds by using Grignard reagent, Malonic ester and
Acetoacetic ester.
GRIGNARD REAGENT
 INTRODUCTION:

The organomagnesium halides (RMgX), known as Grignard

reagents, are useful synthetic intermediates in organic chemistry
for carbon-carbon bond formation. They may be regarded as
polar compounds and are sources of nucleophilic carbanions.
They are prepared by adding an alkyl halide to magnesium
shavings being stirred in anhydrous diethyl ether or THF. The
magnesium is inserted between the carbon and the halogen. The
C-Mg bond in Grignard reagents is covalent and not ionic. The
actual structure of Grignard reagents in solution has been a
matter of much controversy over the years.
 PREPARATION

The carbon atom of organic halide which is directly attached to

the halogen is, of course, electrophilic. This electrophilic
reactivity can be switched to nucleophilic reactivity by
conversion to an organomagnesium halide, i.e., a Grignard
reagent.
 The carbon-magnesium bond in a Grignard reagent is polar and
covalent with carbon being the negative end of the dipole. Thus the
nucleophilicity of carbon in a Grignard reagent. Note also that the
magnesium-halogen bond is largely ionic.
The mechanism of formation of a Grignard reagent is shown
below. It involves radical intermediates. There is one major difference that
should be noted. Grignard formation does not involve a radical chain
mechanism. It is a non-chain radical reaction.
ROLE OF SOLVENT:

Organomagnesium and organolithium compounds are

such strong bases that they will react immediately with any
acid that is present in the reaction mixture-even with very weak
acids such as water and alcohols. When this happens, the
organometallic compound is converted into an alkane.
 This means that Grignard reagents and
organolithium compounds cannot be prepared from
compounds that contain acidic groups (OH, NH2,
NHR, SH, COOH groups). Because even trace
amounts of moisture can destroy an organometallic
compound, it is important that all reagents be dry
when organometallic compounds are being
synthesized and when they react with other
reagents. Diethyl ether is an especially good solvent
for the formation of Grignard reagents because
ethers are non-acidic (aprotic). Grignard reagents
are stable in ethers.
 PROPERTIES
PHYSICAL PROPERTIES:

 Non-Volatile.
 Colourless solids.
 Explosive nature(so isolated when they are in
free state).
 For synthetic uses, they are always prepared and
used in ether solution.
CHEMICAL PROPERTIES:

 C-Mg bond is covalent but highly polar.

 Carbon is more negative than Mg. So the electrons in C-Mg bond
are drawn towards the carbon atom.
 As a result the carbon atom has partial negative charge and the Mg
atom has a partial positive charge.

 The alkyl group in Grignard reagent being electron rich can act as
carbanions or nucleophilic.
 They would attack polarized molecules at points of low electron
density.
 Thus the characteristics reaction of Grignard reagents are
nucleophilic substitution and nucleophilic addition reaction.
 SYNTHETIC USES OF GRIGNARD REAGENT:
REACTIONS WITH COMPOUNDS CONTAINING ACTIVE
HYDROGENS:
Active hydrogen which means the hydrogen is more acidic
than that in alkanes. Compounds like water, amines, alcohols which
contain active hydrogens react with Grignard reagents to form alkanes.
REACTION WITH ALKYL HALIDES:
Grignard reagent reacts with saturated
alkyl halides to form higher alkanes or alkenes.
REACTION WITH ALKYNES:
Terminal alkynes(1-alkynes) reacts with Grignard
reagent to form alkynyl magnesium halides which on
subsequent treatment with alkyl halides form higher alkynes.
REACTION WITH CARBONYL COMPOUNDS:

Addition of a Grignard reagent to a carbonyl

compound is a versatile reaction that leads to the formation
of a new bond. The reaction can produce compounds with a
variety of structures because both the structure of the
carbonyl compound and the structure of the Grignard
reagent can be varied. A Grignard reagent reacts as if it
were a carbanion. Attack of a Grignard reagent on a
carbonyl carbon forms an alkoxide ion that is complexed
with magnesium ion. Addition of water or dilute acid breaks
up the complex.
a) REACTION WITH FORMALDEHYDE:
Grignard reagent reacts with formaldehyde
to form primary alcohols.
b) REACTION WITH OTHER ALDEHYDES:
Grignard reagent reacts with aldehydes other
than formaldehyde to form secondary alcohol.
c) REACTION WITH KETONES:
When a Grignard reagent reacts with a
ketone, the addition product is a tertiary alcohol.
d) REACTION WITH ESTERS:

When an ester reacts with a Grignard

reagent, the first reaction is a nucleophilic acyl substitution
reaction because an ester, unlike an aldehyde or a ketone,
has a group that can be replaced by the Grignard reagent.
The product of the reaction is a ketone. The reaction does
not stop at the ketone stage, however, because ketones are
more reactive than esters toward nucleophilic attack.
Reaction of the ketone with a second molecule of the
Grignard reagent forms a tertiary alcohol. Because the
tertiary alcohol is formed as a result of two successive
reactions with a Grignard reagent, the alcohol has two
identical groups bonded to the tertiary carbon.
REACTION WITH ACID CHLORIDE:

Tertiary alcohols are also formed from

the reaction of two equivalents of a Grignard
reagent with an acyl halide. In theory, we should be
able to stop this reaction at the ketone stage
because a ketone is less reactive than an acyl halide.
However, the Grignard reagent is so reactive that it
can be prevented from reacting with the ketone
only under very carefully controlled conditions.
There are better ways to synthesize ketones.
REACTION WITH CO₂:
Carboxylic acids are formed as a result of
addition of Grignard reagent to CO₂.
REACTION WITH CYANIDE:
Grignard reagent react with cyanide
to give ketone as a product.
REACTION WITH SULPHUR:
In this reaction Grignard reagents
initially react with Sulphur atom gives an
addition product, which on further acidic
hydrolysis to form ethane thiol.
REACTION WITH INORGANIC HALIDES:
The Grignard reagent react with inorganic halides
to give organometallic compounds.
REACTION WITH EPOXIDE:
Epoxides react with Grignard reagent to afford
a primary alcohol with the lengthening of the carbon chain
by two carbon atoms. However, in this case of substituted
epoxides, the attack of the Grignard reagent takes place
from the less substituted ring carbon atom of the epoxides.
SYNTHESIS OF PRIMARY AMINES:
The reaction of chloramines with
organomagnesium halides gives primary
amines.
SYNTHESIS OF ALKYL CYANIDE:
The reaction of alkylmagnesium halides with
cyanogens or cyanogen chloride gives alkyl cyanides.
VINOTH U – 2020311052
KEERTHIRAJ M – 2020311019
GURUKRISHNAN S - 2020311013
ACTIVE METHYLENE
COMPOUNDS

 MALONIC ESTER
 ACETOACETIC ESTER
 ACTIVE METHYLENE
COMPOUNDS
• The class of compounds which contain a methylene
group (-CH2-) directly bonded to two electron
withdrawing groups such as -COCH3, -COOC2H5 , -CN,
are called Active Methylene Compounds.
• This is so because the -CH2- group in them is acidic and
reactive.
• Ethyl acetoacetate (Acetoacetic ester) and Diethyl
malonate (Malonic ester) belong to this class.
MALONIC ESTER
INTRODUCTION:
Other names of MALONIC ESTER: Propanedioic Acid,
Methane Dicarboxylic Acid.

 IUPAC Name : Diethyl Propanedioate

 Chemical formula : C₇H₁₂O₄

MALONIC ESTER:

 The malonic ester synthesis is a chemical

reaction where diethyl malonate or
another ester of malonic acid is alkylated at the
alpha carbon (directly adjacent) to
both carbonyl groups, and then converted to a
substituted acetic acid.
 The major drawback of malonic ester synthesis is
that the alkylation stage can also produce
dialkylated structures.
 This makes separation of products difficult and
yields lower.
 PREPARATION
Diethyl malonate is prepared very conveniently by
boiling sodium or potassium cyanoacetate with alcohol
and concentrated hydrochloric acid.
Cyanoacetate required for this process is
obtained from the following steps
 PHYSICAL PROPERTIES

• Diethyl malonate is a colorless, pleasant-smelling

liquid.
• It is paringly soluble in water, freely soluble in
alcohol and ether.
 CHEMICAL PROPERTIES
1.ACIDITY OF -CH₂- GROUP
( Formation of Salts)
• Diethyl malonate contains a methylene group joined to two carbonyl
groups.
• The H atoms of the -CH₂- group are acidic.
• This is attributed to two factors:
• (a) the electron-attracting power of the electronegative oxygen of
carbonyl group (inductive effect) ; and
• (b) the resonance-stabilization of the resultant cation (diethyl
malonate anion).
Anion Formation
 Resonance Structure
The diethyl malonate anion is highly resonance-stabilized so
that its negative charge is delocalized into the two carbonyl
groups.
 Enolates of β-Dicarbonyl Compounds

In an ester, the negative charge of the conjugate

base is delocalized from the α-carbon atom to
just one oxygen atom. Malonate esters form
such resonance-stabilized enolate ions.
The extent of resonance stabilization of this
compound's conjugate base is depicted by the
three resonance forms below:
 Stepwise Reactions

The Malonic Ester Synthesis Is Comprised Of Five Separate

Reactions.
1. Deprotonation of the ester to form an enolate.
2. SN2 of the enolate upon an alkyl halide, forming a new C-
C bond.
3. Acidic hydrolysis of the ester to give a carboxylic acid.
4. Decarboxylation of the carboxylic acid to give an enol.
5. Tautomerization of the resulting enol to a carboxylic acid.
 Salt Formation

The CH₂ group being sufficiently

acidic, diethyl malonate reacts with a
strong base like sodium ethoxide
(C₂H₅ONa) to form the sodium salt.
Salt formation
 Alkylation
Dietlhyl malonate anion is nucleophilic and
reacts with halides to give diethyl alkylmalonate.
 Hydrolysis
• Diethyl malonate undergoes hydrolysis
with dilute HCI to give malonic acid .
• Similarly, diethyl alkylmalonate gives alkyl
malonic acids.
 Decarboxylation
• Alkyl malonic acids that have two –COOH
groups separated by a carbon, on heating (at
about 150°C) split out a molecule of CO₂ to
give the monocarboxylic acid.
 Synthetic Utilities of Diethyl
Malonate

Diethyl malonate is used in the synthesis

of carboxylic acids, keto acids, α-amino
acids, and barbituric acid.
1.Synthesis of Alkylacetic Acids

This involves the reaction of sodium

diethyl malonate with an alkyl halide
followed by hydrolysis and
decarboxylation.
 REACTANT(RX) PRODUCT

CH₃CH₂COOH
CH₃X (METHYL HALIDE)
(PROPONOIC ACID)

CH₃CH₂CH₂COOH
CH₃CH₂X (ETHYL HALIDE)
(BUTANOIC ACID)

CH₃CH₂CH₂X CH₃CH₂CH₂CH₂COOH
(PROPYL HALIDE) (PENTANOIC ACID)

CH₃CH₂CH₂CH₂X CH₃CH₂CH₂CH₂CH₂COOH
(BUTYL HALIDE) (HEXANOIC ACID)
 2.Synthesis of Dialkylacetic
Acids
Alkylation of sodium diethyl malonate is first
done with RX and then with R’X followed by
hydrolysis and decarboxylation.
 3.Synthesis of Succinic Acids
This involves the reaction of sodium diethyl malonate
with ethyl chloroacetate followed by hydrolysis and
decarboxylation.
 4.Synthesis of Higher Normal
Diacids

This involves the reaction of sodium

diethyl malonate (2 molecules) with an
alkylene diiodide followed by hydrolysis and
decarboxylation gives a normal dicarboxylic
acid.
5.Synthesis of Keto Acids

This involves the reaction of sodium

diethyl malonate with acid halides
followed by hydrolysis and
decarboxylation.
6.Synthesis of α,β -Unsaturated Acid

This involves base catalysed reaction of

diethyl malonate with a carbonyl
compound followed by hydrolysis and
decarboxylation.
 7.Synthesis of α-Amino acids

Glycine (a typical -amino acid) can

be obtained from diethyl malonate
by the following steps .
8.Synthesis of Barbituric Acid

Diethyl malonate reacts with urea to

give barbituric acid.
 Uses Of Malonic Ester
• Diethyl malonate, also known as DEM, is the
diethyl ester of malonic acid.
• It occurs naturally in grapes and strawberries as a
colourless liquid with an apple-like odour, and is used
in perfumes.
• It is also used to synthesize other compounds such as
barbiturates, artificial flavourings, vitamin B1, and
vitamin B6.
• Because of its unique structure, diethyl
malonate is reactive and functions as a
reagent for organic synthesis and to make
products such as barbiturates, pigments, and
agrochemicals.
• Volatile esters are known to have fruity
scents and are often used as fragrances and
flavorings.
ACETOACETIC ESTER

AKASH V – 2020311002
HARRISHCHANDER – 2020311014
JAI NISHANTH – 2020311015
THANUSSH R - 2020311048
 INTRODUCTION
 The other names of Acetoacetic Ester are Ethyl Acetoacetate(EAA) and
Ethyl acetyl acetate

 IUPAC NAME - Ethyl 3-oxobutanoate

MOLECULAR FORMULA - CH3C(O)CH2CO2Et (OR)

CH3COCH2COOC2H5

CHEMICAL FORMULA - C6H10O3

 The organic compound ethyl acetoacetate (EAA) is the ethyl

ester of acetoacetic acid. It is a colorless liquid. It is widely used as
a chemical intermediate in the production of a wide variety of
compounds.
 PREPARATIONS

LABORATORY METHOD:

 It can be prepared by Claisen condensation of ethyl acetate. A mixture

of ethyl acetate and sodium ethoxide (C₂H₅ONa) is heated at 78ᵒC for
8 hours.
 The mixture is then cooled and HCl or acetic acid is added slowly.
 The oily layer is separated, dried and distilled.
 The fraction passing between 178-181ᵒC is ethyl acetoacetate
 It involves base-catalyzed condensation of two ester molecules to form
an alcohol and a β-keto ester. Ethyl acetoacetate is a β-keto ester
 The use of stronger bases, e.g. sodium amide or sodium hydride instead
of sodium ethoxide, often increases the yield.
 MECHANISM

STEP-1(Formation of α−carbanion):-

The hydrogen atoms of methyl group of an ethyl

acetate molecule are weakly acid because of the adjacent
electron-withdrawing ester group. Therefore they form the
corresponding ester anion (I) in presence of strongly basic
ethoxide ions.
STEP-2(Addition):-

The nucleophilic attack of the ester anion

(A) takes place on the carbonyl group of second molecule
of ethyl acetate.
STEP-3(Elimination):-

Now the ethoxide ion will be eliminated

and ethyl acetoacetate will be formed.
The above reaction will be followed by acidification
because the α-hydrogen of ethyl acetoacetate are acidic. It
further reacts with the excess sodium ethoxide to form its
salt. Ethyl acetoacetate is regenerated from its salt upon
acidification.
INDUSTRIAL METHOD:

Ethyl acetoacetate is produced industrially by treatment

of diketene with ethanol. The ketene required as starting
material is obtained by the pyrolysis(heating of an organic
material in the absence of oxygen) of acetone at 700-750ᵒC.
Ethyl acetate is produced industrially by passing ketene
into cold acetone when it dimers to form diketene. The
diketene on subsequent treatment with ethanol produces
ethyl acetoacetate.
 PROPERTIES

PHYSICAL PROPERTIES:

 It is a colourless pleasant smelling liquid.

 Boiling point - 180.8 °C
 Melting point - −45 °C
 Density - 1.021 g/cm3, liquid
 It is sparingly soluble in water but freely soluble in organic
solvent.
 It is neutral to litmus.
 Refractive index of ethyl acetoacetate is n = 1.4194.
CHEMICAL PROPERTIES:

ACIDITY OF METHYLENE HYDROGENS;

FORMATION OF SALTS:

Ethyl Acetoacetate contains a methylene group

(−CH −) flanked by two carbonyl groups. The C−H bond
in CH₂ group is readily ionisable because the proton
removal forms a very stable carbanion.

The acidity of C−H bond of methylene group is

attributed to two factors:
i) INDUCTIVE EFFECT:

The inductive effect caused by the electron

attracting power of the electronegative oxygens of the two
carbonyl groups weakens the C−H bonds. Thus the H
atom can dissociate to give a stable anion.
ii)RESONANCE-STABILIZATION OF CARBANION:

The acidity of the C−H bond is greatly

enhanced because the negative charge in the carbanion is
delocalized into the two carbonyl groups by resonance.
The highly resonance-stabilized carbanion may be
represented as:
FORMATION OF SALT:

Ethyl acetoacetate is appreciably acidic and

when treated with a strong base such as sodium
ethoxide(C₂H₅ONa), forms a sodium salt.
ALKYLATION:

Ethyl acetoacetate anion is nucleophilic

and reacts with alkyl halides(Br, Cl, I) to give alkyl
acetoacetic ester.
HYDROLYSIS OF ETHYL ACETOACETATE:

In presence of KOH, the hydrolysis of

EAA may occur in two ways either ketone or carboxylic
acid as the final product. Based on the product obtained,
the hydrolysis can be categorized as ketonic hydrolysis
and acid hydrolysis.

KETONIC HYDROLYSIS:

When ethyl acetate is hydrolyzed with

dilute HCl, acetoacetic acid is formed. Acetoacetic acid
undergoes decarboxylation on heating.
This type of ethyl acetoacetate(or it alkyl derivative) to give
a ketone is called ketonic hydrolysis.
ACID HYDROLYSIS:

When ethyl acetoacetate is hydrolysed with

concentrated NaOH and then acidified with dilute HCl,
acetic acid is formed.

This type of hydrolysis of ethyl acetoacetate(or its alkyl

derivative ) to give a carboxylic acid is called acid
hydrolysis.
 KETO-ENOL TAUTOMERISM OF ETHYL
ACETOACETATE

Tautomerism is the phenomenon in which two isomeric

forms having different functional group are spontaneously
interconvertible and can exist in dynamic equilibrium. The
two forms in tautomeric equilibrium are called tautomer
of each other. All carbonyl compounds: aldehyde, ketones
and esters exhibit tautomerism. It involves the migration
of a proton from α-carbon to the carbonyl oxygen.
 Ethyl acetoacetate is a tautomeric mixture of keto and
enol forms.

Geuther (1863) suggested the keto structure, while

Frankland and Duppa (1865) independently proposed the
enol structure of ethyl acetoacetate. The presence of each
of the enol and keto forms in ethyl acetoacetate was
supported by two sets of reaction.
REACTION SUPPORTING ENOL FORM:

(i) When acetoacetic ester is treated with metallic

sodium, hydrogen is evolved and the sodium
derivative is formed. This showed the presence of a
hydroxyl group.
(ii) When acetoacetic ester is treated with an ethanolic
solution of bromine, it readily decolourises. This
indicates the presence of an olefinic double bond.

(iii) When acetoacetic ester is treated with ferric

chloride, a reddish-violet colour is produced. This is
characteristic of compounds containing the enolic
group (- C(OH)=C).
(iv) On treatment with PCl₅ , it forms ethyl ester of β-
chloroacetic acid. PCl₅ is used for the conversion of
hydroxyl group into chloro functionality. Hence it has
been again proved from this reaction that hydroxyl
group is present in EAA.
REACTION SUPPORTING KETO FORM:

1. EAA forms addition products with HCN and NahSO3,

indicating presence of carbonyl (>C=O) group by forming
cyanohydrin and bisulphite compound.
2. It reacts with hydroxylamine (NH₂OH) and phenyl
hydrazine (PhNHNH₂ ) to form Oxime and phenyl
hydrazone respectively. Formation of oxime and
hydrazone is characteristic of compound containing
ketone group.
SEPARETION OF KETO AND ENOL FORM:

Ludwing knorr(1911) isolated the two tautomeric forms of

ethyl acetoacetate.

 Keto form was obtained as crystal by cooling a solution

of ordinary ethyl acetoacetate in petroleum ether to -
78ᵒC.

 The enol form was obtained by treating the suspension

of sodium acetoacetic ester in petroleum ether cooled to
-78ᵒC with just enough HCl gas to decompose the
sodium salt. The product was an oily liquid.
1. Reaction that EAA undergo due to presence of
Enolic group:

(a)Reaction with Ammonia and 1ᵒamine/2ᵒamine

EAA on treatment with ammonia or
1ᵒamine or 2ᵒamine gives β-amino crotonic ester
by removal of water molecule.
(b) Reaction with acetyl chloride
EAA in benzene is treated with acetyl chloride to form O-
acetyl derivative of enolic form of EAA. This reaction is an example
of electrophilic substitution reaction.
Reaction with nitrous acid:
EAA on reaction with nitrous acid gives α-oximino
derivative.
 SYNTHETIC USES OF ETHYL ACETOACETATE
Preparation of 2,5-dimethyl pyrrole:
Pyrrole is five membered heterocyclic compound containing
one nitrogen atom. It has been widely in preparation of medicine in
pharma industry.
SYSTHESIS OF 4-METHYL URACIL:
EAA(in its enol form) reacts with urea in the
presence of POCl3 to form 4-methyl uracil, which is
heterocyclic compound.
SYNTHESIS OF ALKYLACETIC ACIDS:
This involves the reaction of sodium
ethyl acetoacetate with an alkyl halide(RX) followed by
acid hydrolysis.
 REACTANT(RX) PRODUCT

CH₃CH₂COOH
CH₃X (METHYL HALIDE)
(PROPONOIC ACID)

CH₃CH₂CH₂COOH
CH₃CH₂X (ETHYL HALIDE)
(BUTANOIC ACID)

CH₃CH₂CH₂X CH₃CH₂CH₂CH₂COOH
(PROPYL HALIDE) (PENTANOIC ACID)

CH₃CH₂CH₂CH₂X CH₃CH₂CH₂CH₂CH₂COOH
(BUTYL HALIDE) (HEXANOIC ACID)
SYNTHESIS OF DIALKYLACETIC ACID:
Alkylation of sodium ethyl acetoacetate is
first done with RX and then with R’X followed by acid
hydrolysis.
SYNTHESIS OF SUCCINIC ACIDS:
The reaction of sodium ethyl acetoacetate
with ethyl chloroacetate (ClCH₂COOC₂H₅) followed
by acid hydrolysis gives succinic acid.
SYNTHESIS OF HIGHER NORMAL DIACIDS:
Higher dicarboxylic acids such as glutaric
acid, adipic acid, pimelic acid, and the like, are prepared
by reaction of two moles of the sodium salt of EAA with
dihaloalkanes (having halogen at the terminal) followed
by acid hydrolysis.
SYNTHESIS OF α,β-UNSATURATED ACIDS:
This involves base catalysed reaction
of ethyl acetoacetate with an aldehyde or a ketone
followed by acid hydrolysis.
SYNTHESIS OF METHYL KETONES:
This involves the reaction of sodium ethyl
acetoacetate with an alkyl halide(RX) followed by
ketonic hydrolysis.
 REACTANT(RX) PRODUCT

CH₃C(O)CH₂CH₃
CH₃X (METHYL HALIDE)
(2-BUTANONE)

CH₃C(O)CH₂CH₂CH₃
CH₃CH₂X (ETHYL HALIDE)
(2-PENTANONE)

CH₃CH₂CH₂X CH₃C(O)CH₂CH₂CH₂CH₃
(PROPYL HALIDE) (2-HEXANONE)
CH₃C(O)CH₂CH₂CH₂CH₂CH
CH₃CH₂CH₂CH₂X
₃
(BUTYL HALIDE)
(2-HEPTANONE)
SYNTHESIS OF 1,3-DIKETONES:
This involves the reaction of sodium ethyl
acetoacetate with acid halides followed by ketonic
hydrolysis.
SYSTHESIS OF ACETONYL ACETONE:
This reaction involves the reaction of 2 moles of
sodium ethyl acetoacetate with iodine followed by ketone
hydrolysis.
SYNTHESIS OF ANTIPYRINE:
Ethyl acetoacetate reacts with
phenylhydrazine to give antipyrine.