Michael Addition reaction M Pharm Pharmaceutical chemistry.pptx

Michael Addition reaction is included in the syllabus of Advance Organic Chemistry M pharm (Pharmaceutical Chemistry) 1st semester

1. CHHATRAPATI SHAHU JI MAHARAJ UNIVERSITY KANPUR TOPIC- STUDY OF MICHAEL ADDITION REACTION Diwakar Kumar Mishra M PHARM 1 ST YEAR PHARMACEUTICAL CHEMISTRY SCHOOL OF PHARMACEUTICAL SCIENCES PRESENTED BY-

2. Topi c Introduction Michael reaction Reaction Mechanism Applications

3. Definition:- Michael Addition can be defined as the nucleophilic addition of a nucleophile (or a carbanion) to an 𝛼,𝛽-unsaturated carbonyl compound, and it belongs to a group of reactions that are considered very useful in the mild formation of carbon- carbon bonds. Michael donor Michael acceptor Enolates of carbonyl compounds will add to an α,β- unsaturated carbonyl compounds to give dicarbonyl compounds. This is called the Michael reaction . INTRODUCTION

4. In this scheme, R and R' on the nucleophile (the Michael donor) represent electron-withdrawing substituents such as acyl and cyano groups, which make the adjacent methylene hydrogen acidic enough to form a carbanion when reacted with the base, B:. The R" substituent on the activated alkene, also called a Michael acceptor, is usually a ketone, Nitro groups.  Michael reaction was first defined by Arthur Michael, an American organic chemist. MICHAEL ADDITION REACTION

5. MECHANISM

6. Michael Addition Mechanism Step 1 :- The carbonyl-containing compound is attacked by the base in the first step of the Michael addition mechanism. Subsequently, the alpha hydrogen of the carbonyl compound is deprotonated by the base, leading to the formation of the carbanion (which has enolate ion). Step 2 :- The electron withdrawing groups of the carbanion give it stability. The enolate ion and the Michael acceptor now react together, leading to the formation of a new carbon- carbon bond. Thus, the enolate ion completes a 1,4 addition on the 𝛼,𝛽-unsaturated carbonyl compound

7. Step 3:- The compound formed from the 1,4 addition of the enolate on the 𝛼,𝛽-unsaturated carbonyl compound is now protonated, giving the required product. The Michael addition mechanism is illustrated above along with the list of bonds formed and broken during the Michael reaction. Thus, the 1,5 dicarbonyl compound is formed from the addition of the enolate of a carbonyl compound to an 𝛼,𝛽- unsaturated carbonyl compound. This product is commonly referred to as a Michael Adduct

8. A well-known Michael reaction is the synthesis of warfarin from 4- hydroxycoumarin and benzylideneacetone It is an anticoagulant. It is commonly used to treat blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1 Base Hydroxycoumarin Warfarin. APPLICATION 1. Preparation of warfarin

9. 2. Formation of methyl acrylate from diethyl malonate

10. The above-shown example is a 1,3-diketone but other electron-withdrawing groups such as esters, nitriles and nitro compounds in the same arrangment can also be Michael donors. Similarly, the electron-withdrawing group of the ɑ, β- unsaturated compound can be any of these as well 3. Formation Michael Donor

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