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.

[/

Comments

Comment section

15 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. 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.

  4. 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.

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.