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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{ 9 comments… read them below or add one }

Joseph McClaren March 19, 2012 at 11:44 am

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 March 19, 2012 at 12:17 pm

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 April 3, 2012 at 7:10 am

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 April 3, 2012 at 12:44 pm

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 April 3, 2012 at 8:53 pm

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

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james April 5, 2012 at 5:51 pm

Generally speaking, yes.

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Ola July 9, 2012 at 12:09 pm

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 July 11, 2012 at 12:30 pm

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 July 20, 2012 at 6:49 am

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

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