Enolate anions, addition reactions resonance stabilization

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Many carbanionic nucleophiles that would be considered too hard to react as Michael donors can be made into effective reagents for conjugate addition reactions by appending resonance or inductively stabilizing groups to soften their intrinsic Lewis basicity. Such stabilized anionic Michael donors include enolates, alkylthio-substituted carbanions, ylides and nitro-substituted carbanions. 

The normal addition process is identical to the other reactions that have been encountered so far in this chapter The nucleophile bonds to the carbonyl carbon and the electrophile bonds to the oxygen of the carbonyl group. In a conjugate addition the nucleophile bonds to the /3-carbon. The electrophile, a proton, can bond to either the a-carbon or the oxygen of the resonance stabilized anion. It actually reacts faster at the oxygen, producing an enol in an overall 1,4-addition. However, as discussed in Section 11.6, ends are less stable than the carbonyl tautomers, so the product that is isolated contains the carbonyl group. 

Mechanism Because the Tr-electron systems of the two functional groups in a,p-unsaturated ketone are conjugated, the radical anion A formed by electron addition from a reducing metal is resonance stabilized. The usual fate of the A is protonation (or other electrophilic bonding) at the P-carbon atom. This creates an enoxy radical B which immediately accepts an electron to form an enolate anion C. Protonation or alkylation of this enolate species then gives a saturated ketone D or E, which may be isolated or further reduced depending on the reaction conditions (Scheme 6.33). 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Thiamine anions add to aldehydes and ketones (e.g., acetaldehyde, carbohydrates, and pyruvic acid). Pyruvic acid adducts decarboxylate with a half-life of 24 hours in water and 3.2 minutes in ethanol, since ethanol cannot stabilize the intermediate zwitterion as well as water. After acidification, acetaldehyde is split off. In the adduct between acetaldehyde and thiamine, the electrophilic carbon atom of the aldehyde undergoes an Umpolung " to a resonance-stabilized enolate carbon atom. The thiazole-bound acetaldehyde then functions as carban-ion in Michael additions under mildly basic conditions. Retro-aldo reactions are observed, when 1,3-thiazolium ions react with the carbonyl groups of carbohy-... 

As you study this mechanism, note how closely its first two steps resemble the first steps of the aldol reaction (Section 15.1). In each reaction, base removes a proton from an a-carbon in Step 1 to form a resonance-stabilized enolate anion. In Step 2, the enolate anion attacks the carbonyl carbon of another ester molecule to form a tetrahedral carbonyl addition intermediate. 

When a nucleophile donates electrons to the C=C unit of the conjugated system, it is commonly called Michael addition (or the Michael reaction), after Arthur Michael (United States 1853-1942). A generalized form of this reaction shows that the conjugated carbonyl compound 43 is attacked by a nucleophile (Y ) to form a new bond (C-Y). Reactions of this type are also called 1,4 addition or conjugate addition. The two donated electrons from Y are used to form this new bond, which leads to breaking the Ji-bond in 43. The two electrons in the n-bond are transferred to the a-carbon to form enolate anion 44, which is resonance stabilized. Workup with aqueous acid gives the isolated product, 45. There are many examples of this reaction, and some of them generate new carbon-carbon bonds when Y is a carbon nucleophile. 

Michael Reaction (Section 19.8A) A Michael reaction involves the addition of a weakly basic nucleophile to a carbon-carbon double bond made electrophilic by conjugation with the carbonyl group of an aldehyde, a ketone, or an ester or with a nitro or cyano group. The mechanism of the Michael reaction involves initial formation of an enolate anion in base and attack of the enolate nucleophile at the )3-carbon of the Michael acceptor to create a new resonance-stabilized enolate anion intermediate that is protonated on oxygen to create an enol and regenerate the base then tautom-erization to the keto form completes the reaction. The base is catalytic in the Michael reaction. 

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