1,4-addition of nucleophiles to enones

by James

Description: Alpha beta unsaturated ketones can undergo reaction with a variety of nucleophiles to form 1,4-addition products (aka “Michael products”)

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Notes: If the nucleophile is negatively charged, such as RO(–), RS(–), HO(–), NC(–) etc., acid will be needed in the second step. If the nucleophile is neutral such as RNH2 or RSH, then the second step will be a proton transfer.

Ketones or aldehydes with an alkene adjacent to them are referred to as “alpha, beta unsaturated”.

Examples:

Notes:

Mechanism: The negatively charged nucleophile attacks the beta carbon of the α,β-unsaturated ketone (C–4 in this case), producing an enolate (Step 1, arrows A and B). Protonation (Step 2, arrows C and D) produces the neutral product.

Notes:

Nothing special about Cl here, it’s just a spectator ion to balance out H3O(+)

The products of these reactions are extremely prone to elimination through E1cb mechanisms, or through tautomerism.

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{ 9 comments… read them below or add one }

Joseph McClaren

Could you please explain some of the terminology that is commonly used for carbonyl chemistry – alpha beta, and especially 1,4. And provide suggestions on keeping things sorted in memory. Or provide a link if you have already done so.

The numbering particularly threw me when I was a student. We had just become comfortable numbering carbons for nomenclature and here comes carbonyl chemistry to derail us.

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james

Good point. It trips a lot of people up. I should write a post and link to it.

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Nima Omid-Fard

What is the reason for strong nucleophiles favoring 1,2 addition while weak nucleophiles favor 1,4 addition? is 1,2 less sterically hindered (kinetic addition product) but 1,4 thermodynamically favored?

Also, enolates, being weak nucleophiles, usually favor adding 1,4 right?

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james

Great question. It has to do with a topic that doesn’t get much discussion in organic chemistry until later on – called “Hard-soft acid-base theory”. Nucleophiles with a concentrated charge density like organolithiums and Grignards tend to add to the atom of the enone with the highest charge density (the carbonyl carbon). For a full explanation I’d need to invoke molecular orbital theory.

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Nima Omid-Fard

I see. Thanks! Do enolates always prefer to add via 1,4 addition?

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james

Generally speaking, yes.

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Ola

I am wondering what would happen if we reacted Alpha beta unsaturated ketone and e.g. morpholine? What would act as a nucleophile: oxygen or nitrogen?
Thanks.

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james

With morpholine, only the nitrogen will be nucleophilic in that case. The oxygen would lead to a positively charged species that cannot become neutral through loss of hydrogen. If you had to compare a molecule with an amine and an alcohol, say, ethanolamine, the nitrogen would be more nucleophilic since nucleophilicity of a lone pair increases as you go to the left along the periodic table (N > O)

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Ola

Thank you for the response. That has cleared things up.

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