C-C bond formation involving aromatic

substitution reactions
By: HARENDRA KUMAR MEHTA
HARSH JOSHI
JAYAKRISHNAN R.
LEYA SAJU
Content
• Skraup Quinoline synthesis
• Vilsmeier-Haack formylation or Vilsmeier reaction.
• Reimer-Tiemann Reaction
 Quinoline
• Quinoline is a heterocyclic aromatic organic compound with the
chemical formula C9H7N.
• Heterocyclic analog of naphthalene which can be obtained by fusing a
benzene ring to pyridine nucleus.

Quinoline Isoquinoline
Anti-cancer

Anti-malarial

Anti-HIV

Parkinson's
Disease

Analgesic

Alzheimer
Therapy

Antifungal

Anti-bacterial
• Quinoline was first extracted from coal tar in 1834 by German chemist Friedlieb
Ferdinand Runge; he called quinoline leuko ("white oil" in Greek).

• Coal tar remains the principal source of commercial quinoline.

• In 1842, French chemist Charles Gerhardt obtained a compound by dry distilling

quinine, strychnine, or cinchonine with potassium hydroxide; he called the
compound Chinoilin or Chinolein.

• The German chemist August Hoffmann eventually recognized that the differences in
behaviors was due to the presence of contaminants and that the two compounds
were actually identical.
Physical properties
• It is a colorless hygroscopic liquid
• Strong odor.
• Aged samples, especially if exposed to light, become yellow and later
brown. •
• Slightly soluble in cold water but dissolves readily in hot water and
most organic solvents
• Density: 1.093 g/mL
• Melting point: -15 °C
• Boiling point: 237 °C
Skraup Quinoline synthesis
• Most well known synthesis of quinoline
• It is the reaction between Aniline and Glycerol, using sulfuric acid and a mild
oxidizing agent like Nitrobenzene

H2SO4
PhNO2

• The reaction tents to be violent, so the modern version of this reaction uses
Fe2(SO4)3 is used as the oxidant with a bit of boric aid
Mechanism
• The reaction starts with the dehydration of Glycerol to form acrolein

H2SO4

- 2H2O

• Then the reaction proceedes by conjugate addition

PhNO2 , -H2
Vilsmeier-Haack formylation or Vilsmeier reaction.
• Formylation of Aromatic ring
• Formylation means insertion of formyl (-CHO) group
• electron rich systems are treated with amides in the presence
of POCl3 to form aryl aldehydes or aryl ketones & amines
Substrate: Electron rich aromatic compounds
Reagent : Substituted amides and acid chloride
Products : Aryl Aldehydes or ketones.

Example:
Electron rich systems
Aromatic systems
• Benzene or Naphthalene bearing electron donating group (EDG) and
Anthracene, electron rich and does not require EDG

Non-Benzenoid systems
Hetrocyclic Systems
Reagents
i. Substituted amides

• R, R1 , R2 = H, alkyl, phenyl, aryl group

• If R2 = H then resulting product bears aldehyde functionality
• If R1 = alky|/phenyl/aryl group then resulting product bears
ketone functionality
• Generally used amides for formulation are,
ii. Acid Chlorides
• Chlorides are produced from organic acids or inorganic acids
• Some chlorinating agents are given below:

Vilsmeier reaction is an example of

Electrophilic substitution
This reaction proceeds with the help of E+
(iminium cation intermediate)

• All of these are chlorinating agents to amides to produce iminium

intermediate cation required for this reaction
Temperature:
• Generally a temperature of about 100 °C is required.
• Temperature varies depending upon nature of reacting species.

Solvent:
• N.N-dimethylformamide (DMF) can act as reactant as well as
solvent because easily removed if excess.
• Generally used solvent is dichloromethane (DCM)

Time:
• Generally time required varies from 10 hours to 24 hours or more.
• Time varies depending upon nature of reacting species
Mechanism: STEP 1
• Amide (here DMF) reacts POCl3 to form Vilsmeier Reagent.
 Mechanism: STEP 2
Reaction of Vielsmeier Reagent with Electron Rich System
Mechanism: STEP 3
Reaction with water(aqueous workup)
Applications
• If we do the reaction on a substituted pyrrole, it get formylated at 2nd
position

DMF, POCl3
Δ

• If we do the reaction on an antracene, it get formylated at 9th position

DMF, POCl3

Δ
• If we do the reaction on a substituted mono substituted benzene with an
electron donating group, it get formylated at ortho and para position, with
major product being the para product

DMF, POCl3
Δ
major minor

• If we do the reaction on an Azulene, it get formylated at 1st position

DMF, POCl3

Δ
Reimer-Tiemann Reaction
▫ It's two German chemists. Karl Reimar and Ferdinard Tiemann
Reimer-Tiemann Reaction is a type of Substitution reaction
It is used for the orthoformylation of phenols.
▫ It is convenient to divide the Reimar Tiemann reaction into a
normal and abnormal transformation upon the reaction product.
Condition for Reimer Tiemann Reaction
Phenols C6H5OH is treated with CHCI3 (chloroform) in the presence of
NaOH (sodium hydroxide) or KOH (potassium hydroxide).

Intermediate
The intermediate involved in Reimer Tieman's reaction is carbene.
Chemical Reaction
Reaction Mechanism

• The chloroform is deprotonated by the strongly basic aqueous hydroxide

solution, giving the chloroform carbanion.
• This chloroform carbanion readily undergoes alpha elimination, giving
dichlorocarbene as the product. Dichlorocarbene is the principle reactive
species.
• The aqueous hydroxide also deprotonates the phenol reactant, yielding a
negatively charged phenoxide.
• This negative charge is now delocalized into the benzene ring, causing it
to be far more nucleophilic.
• This results in a nucleophilic attack on the dichlorocarbene, forming an
intermediate dichloromethyl substituted phenol.
• This intermediate is subjected to basic hydrolysis to finally achieve the
formation of the desired orthohydroxybenzaldehyde.
Mechanism
Step 1: Generation of carbene which acts as an electrophile
Step 2: Base abstracts the hydrogen atom from -OH group to form a phenoxide ion
which is resonance stabilized.

Step 3: Addition of dichlorocarbene to the ring followed by hydrolysis

-OH
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