Nucleophilic Addition to Conjugated Carbonyl Compounds

4 NUCLEOPHILIC ADDITION TO CONJUGATED CARBONYL COMPOUNDS MICHAEL 3,4-ADDITION 

Stable carbanion-enolates can also serve as the nucleophile. 

Problem 17.16 (a) Show the nucleophilic addition of the malonate carbanion to methyl vinyl ketone and the formation of the final keto product. (b) Show how this product can be converted to a 5-ketoacid. 4 

Problem 17.17 Cyanoethylation is the replacement of an acidic a H of a carbonyl compound by a —CH2CH2CN group, using acrylonitrile (CH2=CHCN) and base. Illustrate with cyclohexanone.  

A condensation reaction leads to a product with a new C—C bond. Most often the new bond results from a nucleophilic addition of a reasonably stable carbanion-enolate to the C=0 group (acceptor) of an aldehyde less frequently the C—O group belongs to a ketone or acid derivative. Another acceptor is the C N group of a nitrile. 

The addition of the nucleophilic carbanion-enolate, usually of an aldehyde, to the C=0 group of its parent compound is called an aldol condensation. The product is a /f-hydroxycarbonyl compound. In a mixed aldol condensation the carbanion-enolate of an aldehyde or ketone adds to the C=0 group of a molecule other than its parent. The more general condensation diagrammed above is termed an aldol-type condensation. Since the C, not the O, is the more reactive site in the hybrid, the enolate contributing structure is usually omitted when writing equations for these reactions. This is done even though the enolate is the more stable and makes the major contribution. 

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In certain cases, Michael reactions can take place under acidic conditions. Michael-type addition of radicals to conjugated carbonyl compounds is also known.Radical addition can be catalyzed by Yb(OTf)3, but radicals add under standard conditions as well, even intramolecularly. Electrochemical-initiated Michael additions are known, and aryl halides add in the presence of NiBr2. Michael reactions are sometimes applied to substrates of the type C=C—Z, where the co-products are conjugated systems of the type C=C—Indeed, because of the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this... 

J. Fastrez, Estimation of the Free Energies of Addition of Nucleophiles to Conjugated Carbonyl Compounds and to Acyl Derivatives, J. Am. Chem. Soc. 1977, 99, 7004. 

Prior to protonolysis, the products of conjugate addition to unsaturated carbonyl compounds are enolates and, therefore, potential nucleophiles. A useful extension of the conjugate addition method is to combine it with an alkylation step that adds a substituent at the a position.52 Several examples of this tandem conjugate addition/alkylation procedure are given in Scheme 8.2. 

Nucleophilic addition to the carbonyl carbon of an a,f3-unsaturated Class II carbonyl compound is called direct addition addition to the j8-carbon is called conjugate addition. Whether direct or conjugate addition occurs depends on the nature of the nucleophile, the structure of the carbonyl compound, and the reaction conditions. Nucleophiles that form unstable direct addition products— halide ions, cyanide ion, thiols, alcohols, and amines— form conjugate addition products. Nucleophiles that form stable addition products—hydride ion and carbaiuons—form direct... 

DFT calculations have been used to obtain mechanistic insights into the reaction of sulfur ylides PhHC (S+Me2) with dienals and enones by identifying all key transition states and intermediates along the reaction pathway for the 1,2-, 1,4-, and 1,6-nucleophilic attacks at PhCH=CHCH=CHCH=0 and for the 1,2- and 1,4-attacks at MeCH=CHCOMe. The final outcome of the reaction with both substrates has been found to be decided by the interplay between kinetic and thermodynamic factors. Thus, addition of a semi-stabilized ylide to conjugated carbonyl compounds prefers the 1,4-pathway under thermodynamic conditions, in consonance with the experimental reports. However, the formation of epoxides via a 1,2-addition pathway is equally competitive and could be favoured under kinetic conditions. The 2,3-trans cyclo-propanecarbaldehyde is the major product of the 1,4-addition pathway. The enone also prefers the 1,4-addition. ... 

In these investigations, nucleophilic additions to carbonyl groups and carbonyl group equivalents as well as conjugate 1,4-additions to unsaturated carbonyl compounds have been of great value. In the 1,2-additions, aUyl tin-compounds showed interesting synthetic flexibility. They served well for carbonyl groups but also for acetals as is demonstrated with 316 and 317 [103],... 

The nucleophilic addition product of water to a carbonyl compound is unstable and cannot be isolated. This is true for most products made by nucleophilic addition to a carbonyl by the conjugate base of any strong acid (e.g., H2O, HOR, CH, HS04, etc.)... 

Scheme 3.28 General mechanism for conjugated addition of protic nucleophiles (NuH) to unsaturated carbonyl compounds...

A specific example involving aflatoxins is shown in Box 6.8. We shall see other examples of glutathione reacting as a nucleophile in detoxification reactions, where conjugation is not the result of nucleophilic substitution. For example, it might be nucleophilic addition to an electrophile such as an unsaturated carbonyl compound (see Box 10.20). 

Recall that the LUMO shows which regions of a molecule are most electron deficient, and hence most subject to nucleophilic attack. One such region is over the carbonyl carbon, consistent with the observation that carbonyl compounds undergo nucleophilic addition at the carbonyl carbon. Another region is over the P carbon, again consistent with the known chemistry of a,P-unsaturated carbonyl compounds, in this case conjugate or Michael addition. 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

We are going to extend this idea now and show that other groups besides the carbonyl group can promote nucleophilic addition to alkenes and then extend the idea further into the reactions of allylic and aromatic compounds. First of all we are going to look at other conjugating electron-withdrawing groups. 

The in situ generation of an iminium ion from a carbonyl compound lowers the LUMO energy of the system. Iminium catalysis is comparable to Brpnsted- or Lewis acid activation of carbonyl compounds. The LUMO energy is lowered, the a-CH acidity increases, and nucleophilic additions including conjugate additions as well as pericyclic reactions are facilitated (Eq. 34). 

Addition of a nucleophile to the p carbon, called 1,4-addition or conjugate addition, forms a carbonyl compound. 

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