The Vilsmeier-Haack reaction involves treating an electron-rich aromatic or heterocyclic system with a Vilsmeier reagent, which is formed from an amide like DMF and POCl3, to install a formyl group. The reaction proceeds through an iminium intermediate and takes place around 100°C in a solvent like DCM over 10-24 hours. It is useful for synthesizing aldehydes and ketones from electron-rich aromatic and heterocyclic substrates.

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2. VILSMEIER-HAACK REACTION
Dr. Shahid Rasool Vilsmeier-Haack reaction CHEM5128
Advanced Named Reactions
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3. Key Concepts
• Introduction to Vilsmeier-Haack reaction
• Discussion of reacting species, solvents,
temperature, time
• Explanation of mechanism step by step
• Synthetic applications
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4. Vilsmeier-Haack Reaction:
• Vilsmeier-Haack reaction is also known as Vilsmeier-Haack
formylation or Vilsmeier reaction.
• Formylation means insertion of formyl (-CHO) group
• In broad sense, electron rich systems are treated with amides in
the presence of POCl3 to form aryl aldehydes or aryl ketones &
amines
• An example

5. Electron Rich System:
• Aromatic systems
• Benzene/naphthalene bearing electron donating group (EDG)
• Electron withdrawing group (EWG) decreases rate or side
reaction, –COOH converts intermediate (iminium cation) to acid
chloride
• Anthracene, electron rich and does not require EDG
• Intermolecular cyclization also occurs
Y = EDG

6. Electron Rich System:
• Non-benzenoid systems
• For example, azulene, cyclopentadienyl anion
• Heterocyclic systems
• Five member ring system substitutes at 2- & 5- position (unless
blocking or EWG groups)
• Benzo derivatives like indole
• Intramolecular cyclization
N
H
O S Se
Pyrrole Furan Thiophene Selenophene
Azulene Cyclopentadienyl anion
Indole

7. Substituted amides:
• Basic requirement is amide functionality
• R, R1, R2 = H, alkyl, phenyl, aryl group
• If R2 = H then resulting product bears aldehyde functionality
• If R2 = alkyl/phenyl/aryl group then resulting product bears ketone
functionality
• Generally used amides for formylation are,
N C
R1
R
R2
O
N C
H3C
H3C
H
O
N C
H3C
H
O
N-methylformanilide
N,N-dimethylformamide

8. Acid chlorides:
• Chlorides produced from organic acids or inorganic acids
R C OH
O
R C Cl
O
HO
O
O
OH
HO
O
O
OH
P OHHO
O
OH
P ClCl
O
Cl
S OHHO
O
S ClCl
O
Carboxylic acid Acyl halides
Oxalic acid Oxalyl chloride
Phosphoric acid Phosphoryl chloride or
Phosphorus oxychloride
Sulfurous acid Thionyl chloride or
Sulfurous oxychloride

9. Acid chlorides:
• All of these are chlorinating agents to amides to produce iminium
intermediate cation required for this reaction.

10. Temperature:
• Generally a temperature of about 100 oC is required.
• Temperature varies depending upon nature of reacting species.

11. 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.

12. Mechanism: STEP-1
• Amide (here DMF) reacts POCl3 to form Vilsmeier Reagent.
N C
H3C
H3C
H
O
P
O
Cl Cl
Cl
P
Cl Cl
Cl
OO
N
CH3
CH3
- Cl
P
Cl Cl
OO
N
CH3
CH3
Cl
P
Cl Cl
OO
N
CH3
CH3
Cl
P
Cl Cl
OO
N
CH3
CH3
Cl
DMF
Vilsmeier Reagent

13. Mechanism: STEP-2
• Reaction of Vilsmeier Reagent with Electron Rich System
P
Cl Cl
OO
N
CH3
CH3
Cl
EDG EDG
Cl N
CH3
CH3
H
N C
H3C
H3C
H
O
P
Cl Cl
OO
EDG
Cl N
CH3
CH3
N C
H3C
H3C
H
OH
P
Cl Cl
OO

14. Mechanism: STEP-3
• Reaction with water (aqueous workup)
EDG
N
CH3
CH3
Cl
EDG
Cl N
CH3
CH3
O
H H
EDG
O N
CH3
CH3
H
H
Cl
O
H H
EDG
O N
CH3
CH3H
- H3O
O
H H
H
Cl
Cl
- H2O
EDG
O N
CH3
CH3H
H
EDG
O
N
CH3
CH3
H
H
ClCl
N
CH3
CH3
H
EDG
O
N
CH3
CH3
H
H
Cl

15. Synthetic Applications:

16. Synthetic Applications:

17. Synthetic Applications: