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ChemWiki: The Dynamic Chemistry E-textbook > Organic Chemistry > Organic Chemistry With a Biological Emphasis > Chapter 14: Reactions with stabilized carbanion intermediates II > Section 14.2: Variations on the Michael reaction

Section 14.2: Variations on the Michael reaction

Solutions to exercises

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.

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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. 

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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.

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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. 

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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.

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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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Example  
 
Exercise 14.1: Explain, using mechanistic drawings, why aromatic substitution at the meta position (relative to a carbonyl) is not observed.
 

 
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:

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

 

Example  
 
Exercise 14.2:

a) Draw a complete mechanism for the reaction above, clearly showing how the nitro groups stabilize the negative charge on the intermediate.  

b) 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.

c) Why do you think a flourine substituent is used on the aromatic ring instead of a better leaving group such as bromine or chlorine?

 

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

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

 

Example  
 
Exercise 14.3: Propose a mechanism for the enzymatic reaction shown above.
 

 

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

 

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Last Modified
19:52, 1 Oct 2013

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