Michael addition reaction

By Diwan M. Pharm (pharmaceutical chemistry) DIPSAR

1. Michael Addition Reaction Presented By: Diwan

2. Topic Covered Introduction Mechanism Examples Asymmetric Michael reaction References

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

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.

5. Description: Enolates of carbonyl compounds will add to an α,β -unsaturated carbonyl compounds to give dicarbonyl compounds. This is called the Michael reaction .

6. Mechanism

7. If we draw the  resonance structures  of a simple ɑ,  β -unsaturated carbonyl compound, we see that there are two electrophilic positions:

8. 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.

9. 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.

10. Examples 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.

11. In the next step, the nucleophilic attack on the C=C double bond generates an enolate which after the protonation tautomerizes to the corresponding carbonyl compound :

12. In general,  ɑ,  β -unsaturated carbonyl compounds can undergo a 1,2- or 1,4-addition reaction . 1,2-addtion reactions are all of those where the nucleophile attacks the carbonyl group. For example, the reaction of carbonyl compounds with a  Grignard  or organolithium reagent is 1,2-addtion:

13. Both the Grignard and especially organolithiums are very strong bases, and  stronger bases tend to give 1,2 carbonyl addition reactions while weaker bases give 1,4 conjugate addition.  The basicity and nucleophilicity are mostly parallel for this concept.

14. Both reactions below should yield the same product, but which one would work better?

15. Both are Michael reactions, since it is a nucleophilic addition to an ɑ,  β -unsaturated carbonyl compound. However, the first option is using a regular enolate which is a strong base and not a good Michael donor. Therefore, to obtain better yields, the  second reaction  involving  malonic ester  as a nucleophile  is a better choice .

16. Example Diethyl Malonate to Methyl Acrylates diethyl [2-( methoxycarbonyl )ethyl] malonate diethyl bis [2-( methoxycarbonyl )ethyl] malonate

17. 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 K 1 Base H ydroxycoumarin Warfarin

18. Michael Addition of Imidazole to α, β -Unsaturated Carbonyl/ Cyano Compound The conjugate addition of imidazole with acrylonitrile using Cu( acac )2 provided N-substituted imidazoles in poor yield whereas using Cu( acac )2 in ionic liquid, best yield of product obtained. The use of organic solvents such as toluene and chloroform were less effective in place of ionic liquids, whereas the use of a hydrophilic high polar solvent (such as Dimethyl Sulfoxide , DMSO) resulted in 80% product conversion in the same length of time. Michael addition of imidazoles to α,β -unsaturated compounds using copper(II) acetylacetonate immobilized in ionic liquids

19. Robinson annulation The  Robinson annulation  is a  chemical reaction  used in  organic chemistry  for ring formation. It was discovered by  Robert Robinson  in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. [1]  The method uses a  ketone  and a  methyl vinyl ketone  to form an α,β -unsaturated ketone in a  cyclohexane  ring by a  Michael addition  followed by an  aldol condensation . This procedure is one of the key methods to form fused ring systems

20. Mechanism: Micheal addition Aldole condensation

21. Asymmetric Michael reaction Asymmetric Michael additions involve the enantioselective synthesis of the products. Such reactions can be achieved via chiral phase transfer catalysis. In the reaction between  cyclohexanone  and  β- nitrostyrene  sketched below, the base proline is derivatized and works in conjunction with a protic acid such as  p - toluenesulfonic acid

22. Syn addition  is favored with 99%  ee . In the  transition state  believed to be responsible for this selectivity, the  enamine  (formed between the proline nitrogen and the cycloketone ) and  β- nitrostyrene  are co-facial with the  nitro  group  hydrogen bonded  to the protonated amine in the proline side group

23. References https://en.wikipedia.org/wiki/Michael_reaction  Mather, B.; Viswanathan , K.; Miller, K.; Long, T. (2006). "Michael addition reactions in macromolecular design for emerging technologies “ Michael Addition Mechanism https://byjus.com/chemistry/michael-addition-mechanism/