Vilsmeier haack reaction

C-C bond generation in Organic chemistry

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2. Vilsmeier-Haack reaction Dr. Shahid Rasool   Vilsmeier-Haack reaction   CHEM5128 Advanced Named Reactions   2

3. Key Concepts Introduction to Vilsmeier - Haack reaction Discussion of reacting species, solvents, temperature, time Explanation of mechanism step by step Synthetic applications 3

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 POCl 3 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 Azulene Cyclopentadienyl anion Indole

7. Substituted amides: Basic requirement is amide functionality R, R 1 , R 2 = H, alkyl, phenyl, aryl group If R 2 = H then resulting product bears aldehyde functionality If R 2 = alkyl/phenyl/aryl group then resulting product bears ketone functionality Generally used amides for formylation are, N - methylformanilide N,N - dimethylformamide

8. Acid chlorides: Chlorides produced from organic acids or inorganic acids

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 o C 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 POCl 3 to form Vilsmeier Reagent. Vilsmeier Reagent

13. Mechanism: STEP-2 Reaction of Vilsmeier Reagent with Electron Rich System

14. Mechanism: STEP-3 Reaction with water (aqueous workup)

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