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14.2: Variations on the Michael reaction

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    986
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    14.2A: cis/trans alkene isomerization

    Some enzymes are able to catalyze the stereoisomerization of alkene groups using a Michael addition step. Maleylacetoacetate isomerase catalyzes the following cis to trans alkene isomerization as part of the degradation of the aromatic amino acids phenylalanine and tyrosine.

    Fileimage022.png

    An important player in this reaction is a tripeptide coenzyme called glutathione, commonly abbreviated GSH. The important part of glutathione in terms of its chemical activity is the nucleophilic cysteine thiol group - hence the abbreviation GSH.

    Fileimage023.png

    In effect, GSH is just acting as a 'nucleophile for hire' in the maleylacetoacetate isomerase reaction. In the first step, it attacks the beta-carbon in a Michael addition.

    Fileimage024.png

    Notice what this accomplishes: the Cα-Cβ linkage no longer involves a pi-bond (because Cβ is now sp3-hybridized!) and thus is free to rotate - and it does, by 180o. After rotation is complete, the Michael enolate simply collapses, reforming the Cα-Cβ pi-bond in the trans configuration and eliminating GSH.

    14.2B: Nucleophilic aromatic substitution

    Sometimes, a reaction that starts out with a conjugate addition step ends up as a substitution rather than an addition. These reactions are most common on aromatic rings. A nucleophilic aromatic substitution reaction starts out with a nucleophilic attack on a carbon electrophile that is conjugated to an electron-withdrawing groups such as a carbonyl or (more likely in laboratory reactions) a nitro group, forming an enolate-like intermediate.

    Fileimage025.png

    In a Michael addition, the next step would be protonation. However, this is not what happens in this case!

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    Nucleophilic aromatic substitutions proceed in a completely different direction due to two factors. First, protonation as in a Michael addition would lead to a non-aromatic product, which would be energetically unfavorable (remember that aromatic systems confer a extra degree of stability). Second, substrates in aromatic substitutions have a leaving group (designated 'X' in this general mechanism) at the original site of nucleophilic attack. Instead of abstracting a proton from the solvent, therefore, the reactive electrons return to the aromatic system, simultaneously expelling the leaving group.

    Fileimage027.png

    Nucleophilic aromatic substitution can take place at the para position as well as the ortho position, but not at the meta position.

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    Exercise

    Explain, using mechanistic drawings, why aromatic substitution at the meta position (relative to a carbonyl) is not observed.

    Solutions to exercises

    As one example of a nucleophilic aromatic substitution that is useful in the laboratory, 2,4-dinitro fluorobenzene can be used to specifically alkylate the N-terminal amino acid in a protein:

    Fileimage029.png

    This reaction was developed by Frederick Sanger, a pioneer in protein chemistry.

    Exercise 14.2

    1. Draw a complete mechanism for the reaction above, clearly showing how the nitro groups stabilize the negative charge on the intermediate.
    2. Use a resonance argument to explain how the presence of a second nitro group serves to further activate the aromatic ring for nucleophilic aromatic substitution.
    3. Why do you think a flourine substituent is used on the aromatic ring instead of a better leaving group such as bromine or chlorine?

    Solutions to exercises

    There are a few enzymatic examples of nucleophilic aromatic substitutions - the following step from the biosynthesis of purine nucleosides is a particularly important one.

    Fileimage030.png

    The first step is nucleophilic aromatic substitution, the second is a tautomerization.

    Exercise 14.3

    Propose a mechanism for the enzymatic reaction shown above.

    Solutions to exercises

    14.2C: Synthetic parallel - Michael addition reactions in the laboratory

    Michael addition reactions are also common in the organic synthesis lab. Interestingly, while organolithium reagents (section 13.6D) react with α,β-unsaturated ketones mainly with 1,2 regiochemistry (ie. attack at the carbonyl), Gilman (lithium diorganocopper) reagents add mainly to the beta-carbon. Grignard reagents usually give a mixture of both regiochemical outcomes.

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    Fileimage032.png

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    The Stork enamine (section 13.6A) is also frequently used as a nucleophile in carbon-carbon bond-forming Micheal addition reactions in organic synthesis.

    Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)


    This page titled 14.2: Variations on the Michael reaction is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.


    This page titled 14.2: Variations on the Michael reaction is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Tim Soderberg via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.