Base-Catalyzed Enolization Enolate Anions

Step 1 A proton is abstracted by hydroxide ion from the a carbon atom of the carbonyl componnd. 

Step 2 A water molecule acts as a Brpnsted acid to transfer a proton to the oxygen of the enolate ion. 

Conjugate base of carbonyl compound Water Enol 

FIGURE 18.3 Mechanism of the base-catalyzed enolization of an aldehyde or ketone in aqueous solution. 

The key intermediate in this process, the conjugate base of the carbonyl compound, is referred to as an enolate ion, since it is the conjugate base of an enol. The term enolate is more descriptive of the electron distribution in this intermediate in that oxygen bears a greater share of the negative charge than does the a-carbon atom. 

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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... 

Base-catalyzed enol formation occurs by an acid-base reaction between catalyst and carbonyl compound. The carbonyl compound acts as a weak protic acid and donate. one of its a hydrogens to the base. The resultant anion—an enolate ion—is then reprotonated to yield a neutral compound. Since the enolate ion is a resonance hybrid of two forms, it can be proto-nated either on the a carbon to regenerate the keto tautomer or on oxygen to give the enol tautomer (Figure 22.2, p. 905). 

A variation on the Claisen condensation is an important biochemical reaction responsible for carbon-carbon bond formation in the biosynthesis of fatty acids. Also, a reverse Claisen condensation occurs in the catabolism of fatty acids. We have seen that the base-catalyzed condensation of two car-boxylate esters occurs because the proton a to the carbonyl group is slightly acidic. The a-hydrogen atom in P-keto esters has a pA of about 10.5. This p/f value is too high for P-keto esters to be of much use in biochemical reactions. At pH 7, the ratio of the conjugate base (the enolate anion) to the keto ester is less than 0.001. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

Since cumulenes and alkynes are often easily interconvertible, many syntheses discussed above have allenic counterparts, especially base-catalyzed cyclizations of allenic alcohols.77 And, of course, several of the alkyne-based syntheses may well have allenic intermediates. There are, however, a few syntheses based specifically upon allene chemistry. In an important one, due to Stirling and his collaborators,78 an allenic sulfonium salt reacts with an enolate anion. Scheme 12 sketches the main features yields as high as 86% are recorded. Methoxyallene is easily metallated by butyllithium and so converted into an allenic epoxide that can be isomerized by fe/T-butoxide into a furan (Scheme 13) or an exocyclic equivalent similar to 15 clearly this method is particularly suited to the preparation of 3-methoxyfuran... 

Only Cram (36) has published a rationale for the very high (99%) enantiomeric excess achieved in the reaction of methyl vinyl ketone and the hydrindanone in the presence of the chiral crown ether. This mechanism envisions a bimolecular complex comprising the potassium cation and chiral host as one entity and the enolate anion of the hydrindanone as the counterion. Methyl vinyl ketone lies outside this complex. The quinine-catalyzed reaction appears to have a termo-lecular character, since the hydroxyl of the alkaloid probably hydrogen bonds with the methyl vinyl ketone—enhancing its acceptor properties—while the quin-uclidine nitrogen functions as the base forming the hydrindanone—alkaloid ion pair. 

Three base-catalyzed reactions of such a H s are shown in Fig. 17-1. Since the reactions have the same rate expression, they have the same rate-determining step the removal of an a H to form a stabilized carbanion-enolate anion. The name of this anion indicates that the resonance hybrid has negative charge on C (carbanion) and on O (enolate). 

A novel base-catalyzed Fries-like rearrangement of a 3-acetoxythiophene has been reported (Scheme 149) (79JOC3292). This has been explained as the result of iodide-induced deacylation and subsequent C-acylation of the intermediate enolate anion. Some transformations of 4-hydroxy-2-methylthiophene-3-carboxylic ester are shown in Scheme 150 (69KGS567,75KGS914,71KGS759). 

Enzymologists have freely proposed enolate anions, enols, and enamines as intermediates for many years. Such intermediates have been demonstrated for some nonenzymatic acid- or base-catalyzed reactions, but how can enzymes form enolates at pH 7 without the use of strong acids or bases The microscopic pRa value of an a-hydrogen in a ketone or aldehyde is about 17-20.72 98"... 

Decarboxylation of p-oxoacids. Beta-oxoacids such as oxaloacetic acid and acetoacetic acid are unstable, their decarboxylation being catalyzed by amines, metal ions, and other substances. Catalysis by amines depends upon Schiff base formation,232 while metal ions form chelates in which the metal assists in electron withdrawal to form an enolate anion.233 235... 

Another base-catalyzed reaction is the addition of enolate anions derived from ketones to the 4 position of the pyridine nucleotides (Eq. 15-19). The adducts undergo ring closure and in the presence of oxygen are converted slowly to fluorescent materials. While forming the basis for a useful analytical method for determination of NAD+ (using 2-butanone), these reactions also have created a troublesome enzyme inhibitor from traces of acetone present in commercial NADH.132... 

The mechanism of base-catalyzed dehydration of aldols involves formation of an enolate anion by removal of a proton from the C2 or alpha carbon and subsequent elimination of the hydroxyl group as hydroxide ion ... 

Section 17-1 we can be sure that this is related to enolization. Formation of either the enol or the enolate anion will destroy the asymmetry of the a carbon so that, even if only trace amounts of enol are present at any given time, eventually all of the compound will be racemized. However, the mechanism requires both that there be an a hydrogen and that the center of symmetry be located at this a carbon. Otherwise, acids and bases are ineffective in catalyzing racemization. 

By UV spectroscopy in aqueous buffers, the secondary IE of six deuteriums on the acidity of 2-nitropropane, a((CH3)2CHN02)/Aia((CD3)2CHN02) was found to be 1.233 0.033, or 1.04 per D.60 The IE was attributed to a hyperconjugative interaction, whereby CH3 stabilizes the C=N+ double bond of the conjugate base, despite the anionic character. The secondary kinetic IEs of four deuteriums on the acid-catalyzed enolization (measured from the rate of bromination, but one that should parallel the equilibrium IE on acidity) of cyclopentyl-2,2,5,5-d4 and cyclohexyl-2,2,6,6-d4 phenyl ketones are 1.21 and 1.41, respectively.61... 

The effects of micellization on reactivity have been investigated for a wide variety of ionic organic reactions other than those discussed previously in Sections IV and V, e.g. the Cannizzaro reaction, racemiza-tion, acid catalyzed enolization, base catalyzed hydrolysis of a,]8-un-saturated ketones, and coupling of quinonediimines with phenols. In the case of the Cannizzaro reaction of benzaldehyde (equation 43), the cationic surfactants eicosanyltrimethylammonium bromide and octa-decyltrimethylammonium bromide increased and the anionic surfactant... 

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