Mannich reaction

Mannich reaction introduction, mechanism and applications

1. MANNICH REACTION

2. CONTENTS Introduction Mechanism Applications

3. MANNICH REACTION Introduction The Mannich reaction is aminoalkylation reaction which involves the condensation of an enolizable carbonyl compound with the compound containing active hydrogen with formaldehyde(non- enolizable ) and ammonia or 1 or 2 amines usually as their hydrochlorides ( HCl being used as catalyst) to form aminomethyl or substituted aminomethyl derivatives is known as Mannich reaction. The base, called Mannich base( Alpha,beta -amino carbonyl compound), is usually isolated as its hydrochloride . Aryl amines do not normally respond to this reaction .

4. MANNICH REACTION Introduction With ammonia or primary amines, the reaction may proceed further since the first formed Mannich base still contains hydrogen on the nitogen atom, i.e., active hydrogen . Hence , 2 amine is preferred for the reaction.

5. MANNICH REACTION Introduction Similarly, three successive reactions with ammonia give a tertiary amine . Thus , with a 1 or 2 amine, the reaction may proceed further to give a 3 amine. The compounds containing active hydrogens (compounds that can donate proton)which react include aldehydes, ketones, esters, phenols,nitroalkanes , - and - methyl pyridines, - and - methyl quinolines , acetylenes, etc.

6. MANNICH REACTION Introduction Ketones with active hydrogen are more commonly used. If the compound contains more than one active hydrogen, all of them may be substituted by amino methyl groups .

7. MANNICH REACTION Mechanism

8. MANNICH REACTION Mechanism

9. MANNICH REACTION Mechanism With unsymmetrical ketones the more highly alkylated -carbon is substituted by the aminomethyl group . This is due to the more acidic character of the hydrogen on the more highly alkylated carbon and for that matter due to more facile enolisation .

10. MANNICH REACTION Applications 1. Many important natural products, especially alkaloids, have been synthesized by this reaction. A classical example is Robinson's synthesis of tropinone by a double Mannich condensation and subsequent synthesis of atropine .

11. MANNICH REACTION Applications

12. MANNICH REACTION Applications 2. Decomposition to saturated and unsaturated ketones on reduction and on heating respectively . Quaternary salts give better yield of unsaturated ketones on heating. The reaction is useful for introducing vinyl group.

13. MANNICH REACTION Applications 3. Building up of ring system—The easy elimination of R2NH from Mannich base has synthetic applications . Thus, the unsaturated ketones obtained by heating the quarternary salts may be used for building ring systems .

14. MANNICH REACTION Applications 4 . The imminium salt, being a strong electrophile, replaces the active hydrogens of indole , phenol,nitroalkane , etc., e.g .

15. MANNICH REACTION Applications 5. Tutocaine , a commercially useful anaesthetic , is prepared as below .

16. MANNICH REACTION Applications 6 . Synthesis of tryptophan—The amino acid, tryptophan is synthesized from the quaternary salt of gramine and acetamidomalonic ester .

17. Sanyal,S.N.;Reactions , Rearrangements and Reagents,Bharati bhawan P&D, pg-142-145 REFERENCES: