Enolate anions thermodynamic stability

The preferential -configuration of the enol esters, derived from p-dicarbonyl compounds under phase-transfer conditions, contrasts with the formation of the Z-enol esters when the reaction is carried out by classical procedures using alkali metal alkoxides. In the latter case, the U form of the intermediate enolate anion is stabilized by chelation with the alkali metal cation, thereby promoting the exclusive formation of the Z-enol ester (9) (Scheme 3.5), whereas the formation of the ion-pair with the quaternary ammonium cation allows the carbanion to adopt the thermodynamically more stable sickle or W forms, (7) and (8), which lead to the E-enol esters (10) [54],... 

Reactions involving ketones are generally controlled by the thermodynamic stability of the enolate anion. However, 2-phenylcyclohexanone reacts with bulky Michael acceptors to form the 2,6-regioisomer preferentially [17], indicating that the reaction is mainly kinetically controlled with the approach of the Michael acceptor to the substituted 2-position being sterically hindered. 

Enolization of cationic ketones is accelerated by electrostatic stabilization of the enolate anion. Rate constants for water-, acetate-, and hydroxide ion-catalysed enolization of 2-acetyl- 1-methylpyridinium ion (94) have been measured13811 and compared with a 2-acetylthiazolium ion (95), a simple analogue of 2-acetylthiamine pyrophosphate.13811 For (94), qh = 1.9 x 102 M-1 s 1, about 1.1 x 106 times that for a typical methyl ketone such as acetone. Thermodynamically, it is >108 times more acidic (pAa values of 11.1 vs 19.3). These increases in kinetic and thermodynamic acidity are derived from through-bond and through-space effects, and the implications for enzymatic catalytic sites with proximal, protonatable nitrogen are discussed. The results for (94) suggest a pAa value of 8.8 for (95), a value that cannot be measured directly due to competing hydrolysis. 

Tantalum enolate chemistry shows the dichotomy for the carbonylation reaction " of Cp Ta(CH2R)Cl3 with CO which results in the mono-THF adduct of rj -acyl complex Cp Ta(0=CCH2R)Cl3(THF) for R = t-Bu (the acyl group is anionic) but the isomeric enolate Cp Ta((Z)-7j -OCH=CHR)Cl3 for R = p-Tol. This invites the question of the relative thermodynamic stabilities of metal complexes of RCH2CO and RCHCHO and additionally the question of Z vs. E enolate stabilities. Only for organometalhc compounds (X = [M]) do we find examples where RCH2COX is less stable than RCH=CHOX. 

However, a A H calculation usually predicts the C-reacted compound to be thermodynamically more stable than the Z-reacted compound (mainly because of the greater C-Z bond strength in the C-reacted product compared to the C=C in the Z-reacted). However, this does depend on the relative C-E vs. 0-E bond strength. It is important to determine which is the dominant effect, product formation based upon product thermodynamic stability or upon kinetic direction from HSAB theory. To do this we need to determine whether the reaction is under kinetic or thermodynamic control. Figure 9.1 gives a flowchart for the decision for a common ambident nucleophile, an enolate anion (Z equals oxygen). 

A quantitative understanding of how enzymes catalyze rapid proton abstraction from weakly acidic carbon acids is necessarily achieved by dissecting the effect of active site structure on the values of AG°, the thermodynamic barrier, and AG int, the intrinsic kinetic barrier for formation of the enolate anion intermediate. The structural strategies by which AG° for formation of the enolate anion is reduced sufficiently such that these can be kinetically competent are now understood. In divalent metal ion-independent reactions, e.g., TIM, KSI, and ECH, the intermediate is stabilized by enhanced hydrogen bonding interactions with weakly acidic hydrogen bond donors in divalent metal-dependent reactions, e.g., MR and enolase, the intermediate is stabilized primarily by enhanced electrostatic interactions with... 

The higher rate of O-protonation than that of C-protonation at temperatures when the thermodynamic stability of the oxonium cation is lower than or comparable with that of the C-protonated form has analogies. Thus, mesomeric anions formed by the heterolysis of a-C—H bonds of aliphatic ketones and nitro compounds are usually more readily protonated at O than at C though a thermodynamically less stable tautomer (enol, an acinitro form) is formed. TTiese deviations from the Bronsted principle are explained 34i. 342> O-protonation requiring a smaller rearrangement... 

The facility of the reaction and the stability of the six-membered ring help shift the equilibrium toward 62, leading to 63 as the major product. Remember Le Chatelier s principle (Chapter 18, Section 18.3), which applies in this case because formation of the product removes the enolate anion and shifts the equilibrium. In other words, under thermodynamic conditions, both 60 and 62 are present at equilibrium, and formation of 63 is much faster than formation of 61. If 63 is treated with aqueous acid in a separate chemical step, the product is 64. 

Under these conditions, the more stable enolate anion predominates. The factors that determine the relative stabilities of enolate anions are the same as those that determine the relative stabilities of alkenes the more substituted the double bond of the enolate anion, the greater its stability. Thus, the composition of the enolate anion mbcture formed under conditions of thermodynamic control reflects the relative stabilities of the individual enolate anions. 

By comparing the measured pfC, with the respective chemical structure (Scheme 8.3), it is easy to understand the influence of substituents on the thermodynamic stability of the enolates, and it is hence possible to appreciate which substrates are suitable to be racemized in situ. Indeed a Broensted plot, correlating thermodynamic and kinetic acidities of the analyzed substrates, shows a straight line (Figure 8.1), indicating that there is a direct relation between the enolate stabihty and the deprotonation rate the more stable the enolate, the faster the anion is formed and, consequently, the faster the racemization at the a-carbon occurs. 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

It is not essential to have two anion-stabilizing groups for successful conjugate addition and it is even possible with simple alkali metal (Li, Na, and K) enolates. Lithium enolates are not ideal nucleophiles for thermodynamically controlled conjugate addition. Better results are often observed with sodium or potassium enolates, which are more dissociated and thus more likely to revert. Lithium binds strongly to... 

Recent research by Bergbreiter, Newcomb, Meyers and their respective coworkers has shown that a variety of factors, such as the base, the temperature of deprotonation, and the size of the substituent on nitrogen, control the structure of the metallated imine and ultimately the regiochemistry of the alkylation reaction. In contrast to metal enolates, where the more-substituted species is usually the more thermodynamically stable, less-substituted sy/i-metallated ketimines, e.g. (89), are the most thermodynamically stable of the possible isomers of unsymmetrical systems. An explanation for the greater stability of syn imine anions compared with anti imine anions has been presented by Houk, Fraser and coworkers. ... 

In their study, Jung and co-workers proposed that metalation at the allylic position, followed by epoxide opening led to or-silylalkoxide 176. A 1,2-Brook rearrangement provided resonance-stabilized dienyl anion 177, which underwent retro-1,6-Brook rearrangement to enolate 178. The thermodynamically favored ( )- ,y -unsaturated enal 175 was formed during the aqueous workup. 

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