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21.10: Conjugate Additions: The Michael Reaction

  • Page ID
    183145
  • 1,2 (Direct) versus 1,4 (Conjugate) Addition

    There are two electrophilic sites in alpha,beta-unsaturated carbonyls: the carbonyl carbon and the beta carbon.  The second electrophilic site is created through resonance as shown below.

    ch 23 sect 10 example 1.png

    It is the strength of the nucleophile that determines the dominant reaction pathway.  Strong nucleophiles like Grignard reagents and hydrides will react directly at the carbonyl carbon following the reactivity previously studied.  The strong nucleophile reacts with the carbonyl carbon to produce a tetrahedral intermediate that is protonated to form an alcohol.  The 1,2 direct addition reaction of prop-2-enal with a Grignard reagent is shown as an example below.

    ch 23 sect 10 example 2.png

    In 1,4 conjugate addition, the nucleophile reacts with the carbon β to the carbonyl driving the formation of an enolate ion that tautermerizes back to the carbonyl upon protonation.while the hydrogen is added to the carbon alpha to the carbonyl. 

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    Mechanism for 1,4 conjugate additionEdit section

    1) Nucleophilic reaction at the carbon β to the carbonyl

    4.jpg

    2) Proton Transfer

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    Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen adds to the oxygen in the four position.

    3) Tautomerization

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    Michael Additions

    Enolates are weak nucleophiles and undergo 1,4 addition to α, β-unsaturated carbonyl compounds in a process called a Michael addition. The reaction is named after American chemist Arthur Michael (1853-1942). Two examples are shown below.

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    In combination with alkylations and condensations, the Michael reaction may be used to construct a wide variety of complex molecules from relatively simple starting materials.  The nucleophile is called the Michael Donor and the electrophile (the alpha,beta-unsaturated carbonyl) is called the Michael Acceptor. The table below shows common reagents used for Michael addition reactions.

    ch 23 sect 10 Michael donors acceptors.png

    There are several examples shown below including cyanide as another potential Michael donor. These anions are sufficiently stable that their addition reactions may be presumed reversible. If this is so, the thermodynamic argument used for hetero-nucleophile additions would apply here as well, and would indicate preferential formation of 1,4-addition products. Cyanide addition does not always follow this rule, and aldehydes often give 1,2-products (cyanohydrins). In each case the initial reaction is a Michael addition, and the new carbon-carbon bond is colored magenta. Any subsequent bonds that are formed by other reactions are colored orange.

    Exercise2

    14. Draw the bond-line structures for the products of the reactions below.

    ch 23 sect 10 exercise 14 updated.png

    15.  Specify the reagents needed to perform the following chemical transformation.

    ch 23 sect 10 exercise 15.png

    Answers

    14.

    ch 23 sect 10 exercise 14 solution.png

    15.

    ch 23 sect 10 exercise 15 solution.png

    Robinson Annulations

    Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring-forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist Sir Robert Robinson (1886-1975) who developed it. He received the Nobel prize in chemistry in 1947. Remember that during annulations five and six membered rings are preferred.

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    Exercise

    16.  Draw the product of the reaction with the enamine prepared from cyclopentanone and pyrrolidine, and the following molecules.

    (a)

    (b)

    (c)

    17.  Draw the product of the following reaction.

    23-12-1.png

    Answer

    16.

    (a)

    (b)

    (c)

     

    17.

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