Master Organic Chemistry Reaction Guide

1,4-addition of enolates to enones (“The Michael Reaction”)

Description:

Enolates of carbonyl compounds will add to an α,β-unsaturated carbonyl compounds to give 1,5-dicarbonyl compounds. This is called the Michael reaction.

Notes: 

Enolates are excellent nucleophiles; although a second resonance form is present with the negative charge on oxygen, the resonance form with the negative charge on carbon tends to be more important for determining reactivity.

Examples:

Notes: Note that in each case a carbon-carbon bond is being formed

Mechanism:

Removal of a proton from the ketone with strong base (Step 1, arrows A and B) results in an enolate, which then performs a 1,4-addition on the α,β-unsaturated carbonyl compound (Step 2, arrows C and D), which is then protonated (Step 3, arrows E and F).

Notes:

Sodium here isn’t specifically important, it just balances out the negative charge.


(Advanced) References and Further Reading

The Michael Reaction (or Michael addition) refers to the general addition of nucleophiles to a,b-unsaturated systems in a 1,4 manner rather than 1,2.

  1. Ueber die Addition von Natriumacetessig‐ und Natriummalonsäureäthern zu den Aethern ungesättigter Säuren
    A. Michael, J. Prakt. Chem. 1887 35 (1), 349-356
    DOI: 10.1002/prac.18870350136
    The original paper by Arthur Michael on the addition of carbon nucleophiles to a,b-unsaturated systems. Note that even though Michael was an American chemist at Tufts College (see the very end of the paper), this was still written in German and published in a German journal since German chemistry journals were the best at the time.
  2. The Michael Reaction
    Bergmann, E. D.; Ginsburg, D.; Pappo, R. React. 1959, 10, 179
    DOI: 10.1002/0471264180.or010.03
    Classic review on the Michael Reaction. This also has detailed experimental procedures towards the end, similar to what you might find in Organic Syntheses.
  3. The asymmetric Michael addition reactions using chiral imines
    Jean d’Angelo, Didier Desmaële, Françoise Dumas, André Guingant, Vedejs, E.
    Tetrahedron Asymmetry 1992, 3 (4), 459
    DOI:  10.1016/S0957-4166(00)80251-7
    Michael reactions can also be asymmetric; if you have a chiral imine instead of a carbonyl, then stereoselective 1,4-addition is possible.
  4. The Enantioselective Organocatalytic 1,4-Addition of Electron-Rich Benzenes to α,β-Unsaturated Aldehydes
    Nick A. Paras and and David W. C. MacMillan
    Journal of the American Chemical Society 2002, 124 (27), 7894-7895
    DOI:
    10.1021/ja025981p
    This is a modern twist on the previous reference by Prof. MacMillan, who has made important contributions to organic chemistry. This paper shows that asymmetric Michael additions can be done through chiral imine intermediates by generating the chiral imine in situ using a chiral amine catalyst. The concept is simple and elegant.

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Comments

Comment section

19 thoughts on “1,4-addition of enolates to enones (“The Michael Reaction”)

  1. Thanks for the numbering part James. It was driving me mad.
    Plus, your tip of always making sure to count my Carbons really helps as well.

  2. Hey James! Quick question:I read in Klein’s book that Michael donors have to be an enolate from a di-carbonyl compound (because it’s more stable and less reactive, etc) in order to be selective to strictly undergo 1,4-addition. Is steric hinderance the reason why 1,4-addition prefer to occur in this case?

    Many thanks!

    1. Hi Fiona,

      Here’s a link to James’ explanation of conjugate addition:

      https://www.masterorganicchemistry.com/tips/conjugate-addition/

      I’m just a student, but anytime I have a conjugated ketone, I have to make a decision between 1,2 direct addition and 1,4 conjugate addition. The direct addition is the kinetic product and the conjugate addition is the more stable thermodynamic product.

      1,2 direct addition is only accomplished by “super hero” amazing nucleophiles. These would be nucleophiles like Grignard reagents (MgBr), Hydrides, or ylides like Wittig reagents (PPh3). I’m sure there are more, but in my O-Chem class, those are the only three we have to worry about. If it’s not one of those, it is going to add 1,4.

      Enolates are great nucleophiles, but they are not “super hero” nucleophiles. So, they will readily add 1,4.

      Hope that helps.

  3. Pertaining to the third step of the mechanism after the conjugate addition, could the negative charge on the carbon not also be on the oxygen as the lone pair is in conjugation with the carbonyl group? In that case, protonation would give a hydroxy ketone. Is this correct?

    1. Protonation on carbon would just give the ketone, not the hydroxy ketone. Protonation on oxygen would give the enol, which through a process called “tautomerism”, would quickly convert to the ketone.

  4. If 1,4- addition and 1,2- addition pathways are both possible, how do we decide which one the reaction actually goes through?

    1. Hi Neha,

      I just commented on the same question above, so I’ll tell you how I remember it, as well.

      Here’s a link to James’ explanation of conjugate addition:

      https://www.masterorganicchemistry.com/tips/conjugate-addition/

      I’m just a student, but anytime I have a conjugated ketone, I have to make a decision between 1,2 direct addition and 1,4 conjugate addition. The direct addition is the kinetic product and the conjugate addition is the more stable thermodynamic product.

      1,2 direct addition is only accomplished by “super hero” amazing nucleophiles. These would be nucleophiles like Grignard reagents (MgBr), Hydrides, or ylides like Wittig reagents (PPh3). I’m sure there are more, but in my O-Chem class, those are the only three we have to worry about. If it’s not one of those, it is going to add 1,4.

      Enolates are great nucleophiles, but they are not “super hero” nucleophiles. So, they will readily add 1,4.

      Hope that helps.

  5. What would happen if we used an organometallic reagent (R MgX or R2CuLi) as a nucleophile? Would it give us a 1-4 addition product or will it directly attack the carbonyl carbon? Has the nucleophilic strength anything to do with it?

    1. Well, you’ve just so happened to give the two canonical examples of nucleophiles that will add to different segments of the molecule. If you use R2CuLi, addition gives a 1,4 product with 100% addition to the alkene and no addition to the carbonyl. If you use a Grignard reagent, addition gives a 1,2 product directly to the carbonyl. It’s thought that the highly polarized C-Mg bond has a greater partial negative charge on carbon, and this is attracted to the partial positive charge on the carbonyl. With copper, it’s a longer story, but the alkene pi bond can coordinate to the Cu which is followed by addition to the beta carbon.

  6. Hi! to which type of the reaction Sn2 or E2 Aza-Michael reaction refers to?
    And which step of the reaction is rate limiting?
    Thank you!

    1. That’s an excellent question. I don’t have a good, short answer for you. It might to some extent, but the aldol addition is reversible. With the Michael, you’re breaking a weaker bond (the C-C pi bond versus the C=O pi bond). On a deeper level there are some molecular orbital considerations to consider (hard-soft acid base theory or HSAB) that we generally don’t get into in intro organic. It’s a deep issue and the answer isn’t immediately obvious.

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