Resonance-stabilized carbon enolate

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

The proton transfer equilibrium that interconverts a carbonyl compound and its enol can be catalyzed by bases as well as by acids Figure 18 3 illustrates the roles of hydroxide ion and water m a base catalyzed enolization As m acid catalyzed enolization protons are transferred sequentially rather than m a single step First (step 1) the base abstracts a proton from the a carbon atom to yield an anion This anion is a resonance stabilized species Its negative charge is shared by the a carbon atom and the carbonyl oxygen... 

Enolate ion formation (Section 18.6) An a hydrogen of an aldehyde or a ketone is more acidic than most other protons bound to carbon. Aldehydes and ketones are weak acids, with pK s in the 16 to 20 range. Their enhanced acidity is due to the electron-withdrawing effect of the carbonyl group and the resonance stabilization of the enolate anion. 

Carbonyl compounds are more acidic than alkanes for the same reason that carboxylic acids are more acidic than alcohols (Section 20.2). In both cases, the anions are stabilized by resonance. Enolate ions differ from carboxylate ions, however, in that their two resonance forms are not equivalent—the form with the negative charge on oxygen is lower in energy than the form with the charge on carbon. Nevertheless, the principle behind resonance stabilization is the same in both cases. 

Protonation of the enolate ion is chiefly at the oxygen, which is more negative than the carbon, but this produces the enol, which tautomerizes. So, although the net result of the reaction is addition to a carbon-carbon double bond, the mechanism is 1,4 nucleophilic addition to the C=C—C=0 (or similar) system and is thus very similar to the mechanism of addition to carbon-oxygen double and similar bonds (see Chapter 16). When Z is CN or a C=0 group, it is also possible for Y to attack at this carbon, and this reaction sometimes competes. When it happens, it is called 1,2 addition. 1,4 Addition to these substrates is also known as conjugate addition. The Y ion almost never attacks at the 3 position, since the resulting carbanion would have no resonance stabilization " ... 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

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... 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

Mechanism. Removal of an a-hydrogen from the acetaldehyde by NaOH produces a resonance-stabilized enolate anion. Nucleophilic addition of the enolate to the carbonyl carbon of another acetaldehyde gives an alkoxide tetrahedral intermediate. The resulting alkoxide is protonated by the solvent, water, to give 3-hydroxybutanal and regenerate the hydroxide ion. 

These anhydro-bases are heterocyclic equivalents of enamines and enol ethers and react readily with electrophilic reagents to give products which can often lose a proton to give a new resonance-stabilized anhydro-base. Thus, anhydro-l,2-dimethylpyridinium hydroxide (645) reacts with phenyl isocyanate to give an adduct (646) which is converted to the stabilized product (647 - 648). A similar sequence with carbon disulfide yields the dithio acid (644). 

It is also generally true that the greater the number of contributing resonance forms, the greater will be the resonance stabilization. For this reason die enolate of a yS -diketone has much more resonance stabilization than die enolate of a simple ketone (three resonance forms versus two). The electrons are delocalized over five atoms in the former versus three atoms in the latter. In addition, the electron density on the carbon atom is less in the diketone enolate than in a simple methyl ketone enolate. 

Kinetic and thermodynamic measurements show that 2-phenylacetylthiophene (92a) has a low enol content K = 3.55 x 10 7 (or )K = 6.45).136 The keto and enol tautomers have pKa values of 14.60 and 8.15, respectively. Relative to a phenyl or furanyl substituent at the carbonyl carbon, the thiophene increases the acidity of the enol tautomer, but stabilizes the ketone, probably via the resonance contribution (92b). Thus 2-thiophenyl stabilizes the enolate by electron attraction, but the ketone by donation. Effects of micelles on the equilibria are also reported. 

The aldol and Claisen reactions both achieve carbon-carbon bond formation and in typical base-catalysed chemical reactions depend on the generation of a resonance-stabilized enolate anion from a suitable carbonyl system (Figure 2.7). Whether an aldol-type or Claisen-type product is formed depends on the nature of X and its potential as a leaving group. Thus, chemically, two molecules... 

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. 

In the presence of strong bases, ketones and aldehydes act as weak proton acids. A proton on the a carbon atom is abstracted to form a resonance-stabilized enolate ion with the negative charge spread over a carbon atom and an oxygen atom. Reprotonation can occur either on the a carbon (returning to the keto form) or on the oxygen atom, giving a vinyl alcohol, the enol form. 

A carbonyl group dramatically increases the acidity of the protons on the a carbon atom because deprotonation gives a resonance-stabilized enolate ion. Most of the enolate ion s negative charge resides on the electronegative oxygen atom. The pKa for removal of an a proton from a typical ketone or aldehyde is about 20, showing that a typical ketone or aldehyde is much more acidic than an alkane or an alkene (pKa > 40), or even an alkyne (pKa = 25). Still, a ketone or aldehyde is less acidic than water (pKa = 15.7) or an alcohol (pA a = 16 to 18). When a simple ketone or aldehyde is treated with hydroxide ion or an alkoxide ion, the equilibrium mixture contains only a small fraction of the deprotonated, enolate form. 

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). 

A second general reaction of aldehydes and ketones involves reaction at the a carbon. A C-H bond on the a carbon to a carbonyl group is more acidic than many other C-H bonds, because reaction with base forms a resonance-stabilized enolate anion. 

C-H bond on the a carbon is more acidic than many other sp hybridized C-H bonds, because the resulting enolate is resonance stabilized. Moreover, one of the resonance structures is especially stable because it places a negative charge on an electronegative oxygen atom. 

The acetone enolate is resonance stabilized. The negative charge is delocalized on the oxygen atom (pale red) and the carbon atom (pale green). 

Enolates are nucleophiles, and as such they react with many electrophiles. Because an eno-late is resonance stabilized, however, it has two reactive sites— the carbon and oxygen atoms that bear the negative charge. A nucleophile with two reactive sites is called an ambident nucleophile. In theory, each of these atoms could react with an electrophile to form two different products, one with a new bond to carbon, and one with a new bond to oxygen. 

In Step [1], the base removes a proton from the a carbon to form a resonance-stabilized enolate. 

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