Formation of Enols and Enolates

FIGURE 17.4 Acid/base eguilibrium of enols and enolates. 

In compounds that can enolize, the proportions of enol vary widely at equilibrium. We can identify a number of factors that influence the equilibrium. The most effective is the achievement of aromaticity by enolization. Thus, 17.6 is unknown—the equilibrium is entirely in favor of phenol. That said, the reaction of phenol with electrophiles (17.7) has a strong resemblance to many of the reactions of enols with electrophiles that we will meet. 

Solvents and temperature also affect the proportions of enol. Thus pentane-2,4-dione contains 80 % enol as a neat liquid, but in water, it is only 15 % enolized. The equilibrium is shifted because water hydrogen bonds so strongly to the keto form. An increase in temperature also favors the keto form, but this is not a large effect at the temperatures at which ordinary organic reactions are carried out. The rate of ketone/enol interconversion depends strongly on pH, and the individual tautomers of pentane-2,4-dione have been isolated at low temperature, under strictly neutral conditions. Other carbonyl compounds, including esters and amides, can and do enolize, but with much more difficulty. For example, neat diethylmalonate (diethyl propanedioate, 17.13) contains only 0.01 % enol at equilibrium, in contrast to the 80 % for pentane-2,4-dione. 

If each of the following molecules was treated with DO /DjO, where, if anywhere, would you expect deuterium to be incorporated  

Two of the compounds can be ruled out of contention immediately as they have no hydrogen atoms at the a-position, viz., PhCHO and MejCCHO. In cyclohexanone, all the a-positions are deuterated, and the same is true for 2,5-dimethylcyclohexanone  

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Alpha substitutions and condensations of carbonyl compounds are some of the most common methods for forming carbon-carbon bonds. These types of reactions are common in biochemical pathways, particularly in the biosynthesis and metabolism of carbohydrates and fats. A wide variety of compounds can participate as nucleophiles or electrophiles (or both) in these reactions, and many useful products can be made. We begin our study of these reactions by considering the structure and formation of enols and enolate ions. 

M.p. 190-192 C. The enolic form of 3-oxo-L-gulofuranolactone. It can be prepared by synthesis from glucose, or extracted from plant sources such as rose hips, blackcurrants or citrus fruits. Easily oxidized. It is essential for the formation of collagen and intercellular material, bone and teeth, and for the healing of wounds. It is used in the treatment of scurvy. Man is one of the few mammals unable to manufacture ascorbic acid in his liver. Used as a photographic developing agent in alkaline solution. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Another example of enzyme- and acid-catalyzed DKR has been reported by Bornscheuer [45]. Acyloins were racemized by using an acidic resin through the formation of enol intermediates. The enzymatic resolution was catalyzed by CALB. Since deactivation of this enzyme occurred in the presence of the acidic resin, they designed a simple reactor setup with two glass vials cormected via a pump to achieve a spatial separation between the acidic resin and the enzyme (Figure 4.20). 

However, the observations of Ward and Sherman need not rule out triple-bond participation and vinyl cations in the systems studied by Hanack and co-workers (75-79). Presumably, the enol formate 61 itself arises via a transition state involving a rate-determining protonation and vinyl cation 62 (see previous section). A vinyl cation such as 62 with an adjacent phenyl group is considerably more stable and hence more accessible than a vinyl cation such as 63, stabilized only by a neighboring alkyl group. Hence, formation of enol formate 61 and its... 

See Section 362 (Ester-Alkene) for the formation of enol esters and Section 367 (Ether-Alkenes) for the formation of enol ethers. Many of the methods in Section 60A (Protection of Aldehydes) are also applicable to ketones. 

C in CH2CI2, in the formation of enol ethers 404 in high yields [26] (Scheme 5.4). Likewise, silylated alcohols 13 and free 1,2- and 1,3-glycols react with ketones in the presence of TMSOTf 20 to cyclic ketals [27]. 

Similar cis stereoselectivity was observed in formation of four- and five-membered rings.86 The origin of this stereoselectivity was probed systematically by a study in which a methyl substituent was placed at the C(3), C(4), C(5), and C(6) positions of ethyl 7-bromoheptanoate. Good (>93%) stereoselectivity was noted for all but the C(5) derivative.87 These results are consistent with a chairlike TS with the enolate in an equatorial-like position. In each case the additional methyl group can occupy an equatorial position. The reduced selectivity of the 5-methyl isomer may be due to the fact that the methyl group is farther from the reaction site than in the other cases. 

The intramolecular version of ester condensation is called the Dieckmann condensation.217 It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 25.218 Only 27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 27 by the reversible condensation mechanism. 

Selenski investigated the use of chiral enol ether auxiliaries in order to adapt method F-H for enantioselective syntheses. After surveying a variety of substituted and unsubstituted enol ethers derived from a vast assortment of readily available chiral alcohols, she chose to employ enol ethers derived from trans-1,2-phenylcyclohexanol such as 73 and 74 (Fig. 4.37). These derivatives were found to undergo highly diastereoselective cycloadditions resulting in the formation of 75 and 76 in respective... 

From the reactions shown in Scheme 5, it is obvious that only those uronic acid derivatives whose elimination proceeds with the formation of enolic or aldehydic groups, or both, afford products capable of reducing the Cu(II) ion. Although such structures can be expected from hexo- and hepto-furanuronic, as well as from hep-topyranuronic, acid derivatives, glycosides of pentofuranuronic and of hexopyranuronic acid derivatives do not exhibit reducing properties. However, in view of this generalization, the zero reducing power observed for compound 26 requires a different explanation. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

It is not only the esters of organic acids which combine, in the manner of the ethyl acetoacetate synthesis , with the enolates of ketones and of esters an analogous behaviour is shown by the esters of nitrous and nitric, acids. The process which leads to the formation of isonitroso-and atinitro-compounds yields products fundamentally similar to those already described just as with ethyl acetate the group CO.CHs enters, so here, the NO- and N02-groups are involved, and enolise " exactly as does >O=0 ... 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

We start the scheme after the oxidative addition of diphenylsilane and coordination of acetophenone has taken place, after the classic mechanism by Ojima [28], The formation of enol ethers proves, that at least for this part of the products formed (up to 22%, Brunner [27], 40% [29]), the reaction proceeds... 

Holmes, J.L. Lossing, F.P. Gas-Phase Heats of Formation of Keto and Enol Ions of Carbonyl Compounds. J. Am. Chem. Soc. 1980,102,1591-1595. 

We can now consider the reaction between the chiral aldehyde (-)-TO with the chiral enolate (5)-74b (Scheme 9.25). This aldol condensation affords two diastereomers 81 and 82 in a ratio of >100 1. A change in the chirality of the enolate reverses the result. Thus, the reaction of (-)-TO with t/ )-74b leads to the formation of 81 and 2 in a ratio of 1 30, favouring therefore with respect to 81. 

Probably the most significant examples of carbon nucleophiles are enolate anions. These can participate in a wide variety of important reactions, and simple nucleophilic substitution reactions are included amongst these. However, we shall consider these reactions at a later stage, when the nature and formation of enolate anions is discussed (see Chapter 10). 

Aldehydes and ketones nndergo acid- and base-catalysed halogenation in the a position. This is also dependent on enolization or the formation of enolate anions. 

The formation of 102 and 103 can be explained if one assumes that deprotonation at C(5) or at C(l ) occurred with similar reaction rates to afford the enolates A and B (Scheme 24). Evidence for this assumption is the finding that upon treatment with one equivalent of base (data not shown), the... 

Any process that produces an enol, including the formation of enolate anions. Enols (i.e., entities containing the moiety HO—C(Ri)=C(R2Rs)) appear as intermediates in a wide variety of enzyme-catalyzed reactions, and Rose has presented the following diagram to describe... 

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