Enols, equilibrium with carbonyl compounds

In this section more mechanistic detail is provided concerning the isomerization of vinyl alcohols (enols) to carbonyl compounds. This isomerization, although it favors the keto structure, allows small concentrations of enols to be in equilibrium with carbonyl compounds, and these enols can lead to productive chemical reactions. 

The next two entries in Table 8.6 (items 23 and 24) involve the addition of enolate anions to alkylating reagents (although there is a complicating second step in item 24). While additional discussion of such systems will be provided when carbonyl compounds themselves are discussed (Chapter 9), these examples are inserted here to demonstrate how enols, closely related to alcohols (yet derived from and in equilibrium with carbonyl compounds), exhibit both similar and different reactiv-ites. There are several unifying features to all of these reactions. 

Now that we know something of the origins of enols and enolates, and we have seen that enols are in equilibrium with carbonyl compounds, it is time to move on to a look at reactions of these species. 

Non-fluxional vinylic boranes do not react with carbonyl compounds. Nevertheless, the vinylic borane 29 reacts with acetone (2 h under reflux) yielding the Z-isomer of the homoallylic borinic ester 30b. The cw-configuration of the reaction product 30b corresponds to the following sequence of transformations (Scheme 2.11). The [1,7]-H shift in the vinylic borane 29 gives the allylic Z, Z-isomer 28d which immediately reacts with acetone before the equilibrium among the allylic isomers is established. On the other hand, cyclopentanone reacts directly with 29 under mild conditions yielding Z, Z-1,3,5-heptatriene 31 and borinic ester 32 (Scheme 2.12). Apparently 29 reacts with the enol form of cyclopentanone, and a direct splitting of the B-Q ,2 bond takes place. Similar reaction of 29 with acetic acid was used for the preparative synthesis of previously unknown hydrocarbon 31 (Scheme 2.12) [35]. 

Notice that the steps in the enol — acetaldehyde reaction are simply the reverse of the acetaldehyde — enol reaction (Fig. 19.15). Note also that in acid, as in base, aldehydes and ketones that have a hydrogens are in equilibrium with their enol forms. We will soon see that although enols are in equilibrium with the related keto forms, it is usually the keto forms that are favored. This equilibrium is called the keto-enol tautomerization.The carbonyl compound and its associated enol are called tautomers. 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

Other compounds with reactive methylene and methyl groups are completely analogous to the nitroalkanes. Compounds with ketonic carbonyl groups are the most important. Their simplest representatives, formaldehyde and acetone, were considered for many decades to be unreactive with diazonium ions until Allan and Podstata (1960) demonstrated that acetone does react. Its reactivity is much lower, however, than that of 2-nitropropane, as seen from the extremely low enolization equilibrium constant of acetone ( E = 0.9 x 10-7, Guthrie and Cullimore, 1979 Guthrie, 1979) and its low CH acidity (pK = 19.1 0.5, Guthrie et al., 1982). ... 

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 ... 

In general, the position of equilibrium for interconversion of a carbonyl compound with the corresponding alkenol (or enol), having the hydroxyl group attached to the double bond, lies far on the side of the carbonyl compound ... 

Today reactions of etiolates are usually carried out much differently by utilizing very strong, nonnucleophilic bases for generating the enolate nucleophile. Instead of having only small equilibrium concentrations of an enolate produced in solution, the use of strong, nonnucleophilic bases like LDA, KHMDS, and KH that have pAYs >35 permits carbonyl compounds, whose a protons have pA"a s of 20-25, to be converted completely to enolate anions. Doing so completely converts the carbonyl compound into a nucleophile which cannot condense with itself and is stable in solution. This enolate can then be reacted with a second carbonyl compound in a subsequent step to give product ... 

Carbonyl compounds such as acetone 10 exist predominantly in the keto form 10 but are in equilibrium with the enol form 11. We shall be more interested in the formation of the enolate anion 13 with base 12 and its reactions at the a-carbon with carbon electrophiles. 

These are the easiest to control as five- and six-membered rings are preferred. If that is what we want, we should use the equilibrium methods we have met so far and allow the molecule to find its own way to the most stable product. Four different enolates 7, 8, 12 and 13 could be made from the diketone 10 by removal of four different protons. Each could cyclise onto the other carbonyl group to give three-membered rings 9 or 11 or five-membered rings 6 or 14. These alkoxides are all in equilibrium with 10 via the enolates and so the unstable three-membered rings quickly revert to 10. So which compound is formed 6 or 14 ... 

According to Section 12.3 enamines are just one synthetic equivalent for enols that are not sufficiently represented in equilibrium with a carhonyl compound to allow for a-functional-izations. Enol ethers and silyl enol ethers, which are addressed in this section, are other synthetic equivalents for such enols. An enol ether, for example, is used as an enol equivalent for aldehyde enols, since several aldehydes do not form stable enamines. In addition, enol ethers or silyl enol ethers are usually employed as synthetic equivalents for the enols of ,/i-unsatu-rated carbonyl compounds. The attempt to react ce,/ -unsaturated carhonyl compounds with secondary amines to give a dienamine is often frustrated by a competing 1,4-addition of the amine. The combination of these factors turns the dienol ether B of Figure 12.23 into a species for which there is no analog in enamine chemistry. 

In contrast to kinetic data, thermodynamic data on enol and enolate formation are far more scarce. This results from the usually very low enol and enolate stabilities which, at equilibrium, make it difficult to measure their proportions relative to the carbonyl compound. This section deals with available data on keto-enol equilibria as well as on acidity constants of the two tautomers. 

For simple carbonyl compounds, the equilibrium between an aldehyde or a ketone and its corresponding enol is usually so shifted towards the keto form that the amount of enol at equilibrium can neither be measured nor detected by spectroscopy. Nevertheless, as recently emphasised by Hart (1979), this does not mean that the enol cannot exist free, not in equilibrium with ketones and aldehydes. Several examples of kinetically stable enols in the gas phase or in aprotic solvents have been reported. Broadly speaking, it appears that enols have relatively large life-times when they are prepared in proton-free media [e.g. the half-life of acetone enol was reported to be 14 s in acetonitrile (Laroff and Fischer, 1973 Blank et al., 1975) and 200 s in the gas phase (MacMillan et al., 1964)]. These life-times are related to an enhanced intramolecular rearrangement, indicated by the very high energies of activation (85 kcal mol-1 for acetaldehyde-vinyl alcohol tautomerization) which have been calculated (Bouma et al., 1977 Klopman and Andreozzi, 1979) It has therefore been possible to determine most of the spectroscopic properties of simple enols [ H nmr,l3C nmr (CIDNP technique), IR and microwave spectra of vinyl alcohol... 

Since carbonyl compounds are in equilibrium with enol ethers in alcohol solution (50), a priori it can be expected that reactions which usually proceed... 

Even though the equilibrium concentration of the enolate ion may be small, it serves as a useful, reactive nucleophile. When an enolate reacts with an electrophile (other than a proton), the enolate concentration decreases, and the equilibrium shifts to the right (Figure 22-1). Eventually, all the carbonyl compound reacts via a low concentration of the enolate ion. 

Sometimes this equilibrium mixture of enolate and base won t work, usually because the base (hydroxide or alkoxide) reacts with the electrophile faster than the enolate does. In these cases, we need a base that reacts completely to convert the carbonyl compound to its enolate before adding the electrophile. Although sodium hydroxide and alkoxides are not sufficiently basic, powerful bases are available to convert a carbonyl compound completely to its enolate. The most effective and useful base for this purpose is lithium diisopropylamide (LDA), the lithium salt of diisopropylamine. LDA is made by using an alkyllithium reagent to deprotonate diisopropylamine. 

When we were looking at spectra of carbonyl compounds in Chapter 15 we saw no signs of enols in IR or NMR spectra. Dimedone is exceptional—although any carbonyl compound with protons adjacent to the carbonyl group can enolize, simpler carbonyl compounds like cyclohexanone or acetone have only a trace of enol present under ordinary conditions. The equilibrium lies well over towards the keto form (the equilibrium con-... 

If you run the NMR spectrum of a simple carbonyl compound (for example, 1-phenyl-propan-1-one, propiophenone ) in D2O, the signal for protons next to the carbonyl group very slowly disappears. If the compound is isolated from the solution afterwards, the mass spectrum shows that those hydrogen atoms have been replaced by deuterium atoms there is a peak at (M + 1)+ or (M + 2)+ instead of at AT1-. To start with, the same keto-enol equilibrium is set up. 

The silyl enol ether can be prepared from its parent carbonyl compound by forming a small equilibrium concentration of enolate ion with weak base such as a tertiary amine and trapping the enolate with the very efficient oxygen electrophile MejSiCl. The silyl enol ether is stable enough to be isolated but is usually used immediately without storing. 

Enamines are not generally used in aldol condensations, partly because they are not reactive enough, but mainly because they are too much in equilibrium with the carbonyl compound itself and exchange would lead to self-condensation and the wrong cross-couplings. You will see in the next chapter that enamines come into their own when we want to acylate enols with the much more reactive acid chlorides. 

In the equilibrium method, the carbonyl compound(s) must be treated with weak, usually aqueous or alcoholic, acid or base and allowed to equilibrate with all possible enols or enolates. Either only one product is possible (due to symmetry or blocking of a positions) or some thermodynamic factor (such as the formation of a stable conjugated enone) ensures that the reaction goes down one preferred route. 

This adduct is in equilibrium with the stable enolate from the keto-ester and elimination now gives an unsaturated carbonyl compound. Such chemistry is associated with the aidol reactions we discussed in Chapter 27. The new enone has two carbonyl groups at one end of the double bond and is therefore a very good Michael acceptor (Chapter 29). A second molecule of enolate does a conju-... 

This vanadium method enables the cross-coupling only in combinations of silyl enol ethers having a large difference in reactivity toward radicals and in their reducing ability. To accomplish the crosscoupling reaction of two carbonyl compounds, we tried the reaction of silyl enol ethers and a-stannyl esters based on the following consideration. a-Stannyl esters (keto form) are known to be in equilibrium with the enol form such as stannyl enol ethers, but the equilibrium is mostly shifted toward the keto form. When a mixture of an a-stannyl ester such as 45 and a silyl enol ether is oxidized, it is very likely that the stannyl enol ether will be oxidized preferentially to the silyl enol ether. The cation radical of 45 apparently cleaves immediately giving an a-keto radical, which reacts with the silyl enol ether selectively because of the low concentration of the stannyl enol... 

Enol (Sections 8.4, 22.1) A vinylic alcohol that is in equilibrium with a carbonyl compound. 

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