Enolate anions, kinetic

In a reaction under kinetic control, the composition of the product mixture is determined by the relative rates of formation of each product. No equilibrium among possible alternative structures is set up. In the case of formation of enolate anions, kinetic control refers to the relative rates of removal of the alternative a-hydrogens. The less hindered a-hydrogen is removed more rapidly thus, the major product is the less substituted enolate anion. Because a slight excess of base is used, there is no ketone to serve as a proton donor and the less stable enolate anion cannot equilibrate with a more stable one. 

Each act of proton abstraction from the a carbon converts a chiral molecule to an achi ral enol or enolate ion The sp hybridized carbon that is the chirality center m the start mg ketone becomes sp hybridized m the enol or enolate Careful kinetic studies have established that the rate of loss of optical activity of sec butyl phenyl ketone is equal to Its rate of hydrogen-deuterium exchange its rate of brommation and its rate of lodma tion In each case the rate determining step is conversion of the starting ketone to the enol or enolate anion... 

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. 

By analogy with the kinetic protonation of steroidal zl -enolate anions with weak acids such as acetic acid, which proceeds at the C-4 atom, since the maximum negative charge resides at this position (54,55), the kinetic protonation of the -dienamines with weak acids also occurs at this... 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

Among Michael acceptors that have been shown to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilylvinyl ketone,295 methyl a-methylthioacrylate,296 methyl methylthiovinyl sulfoxide,297 and ethyl a-cyanoacrylate.298 Each of these acceptors benefits from a second anion-stabilizing substituent. The latter class of acceptors has been found to be capable of generating contiguous quaternary carbon centers. 

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. 

Enolate anion 68, which was generated by kinetic deprotonation of ketone 67, produced CF3 ketone 70 almost exclusively, while enolate anion 69, generated by thermodynamic deprotonation, gave a 3 4 mixture of 70 and 71 (Eq. 36). 

These enzymes do not catalyze any proton exchange at C-3 of pyruvate or at C-2 of an acyl-CoA unless the biotin is first carboxylated. This suggested that removal of the proton to the biotin oxygen and carboxylation might be synchronous. However, 13C and 2H kinetic isotope effects and studies of 3H exchange66 support the existence of a discrete enolate anion intermediate as shown in Eq. 14-11.165/67 This mechanism is also consistent with the observation that propionyl-CoA... 

Alkylation Alkylation of the phenylindanone 31 with catalyst 3a by the Merck group demonstrates the reward that can accompany a careful and systematic study of a particular phase-transfer reaction (Scheme 10.3) [5d,5f,9,36], The numerous reaction variables were optimized and the kinetics and mechanism of the reaction were studied in detail. It has been proposed that the chiral induction step involves an ion-pair in which the enolate anion fits on top of the catalyst and is positioned by electrostatic and hydrogen-bonding effects as well as 71—71 stacking interactions between the aromatic rings in the catalyst and the enolate. The electrophile then preferentially approaches the ion-pair from the top (front) face, because the catalyst effectively shields the bottom-face approach. A crystal structure of the catalyst as well as calculations of the catalyst-enolate complex support this interpretation [9a,91]. Alkylations of related active methine compounds, such as 33 to 34 (Scheme 10.3), have also appeared [10,11]. 

Studies of relative rates, activation parameters, kinetic isotope, and solvent isotope effects, and correlation of rates with an acidity function, have elucidated the mechanisms of cyclization of diacetyl aromatics (23-26) promoted by tetramethyl-ammonium hydroxide in DMSO.32 Rate-determining base-catalysed enolate anion formation from (24-26) is followed by relatively rigid intramolecular nucleophilic attack and dehydration whereas the cyclization step is rate determining for (23). 

Strong bases in dry solvents are usually used in organic synthesis to generate reactive enol anions from ketones. Nevertheless, the kinetic studies discussed here were mostly performed on aqueous solutions. Apart from the relevance of this medium for biochemical reactions and green chemistry, it has the advantage of a well-defined pH-scale permitting quantitative studies of acid and base catalysis. 

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. 

Deprotonation of an unsymmetrically substituted ketone such as 2-methylcyclohexanone (Figure Si3.2) potentially gives rise to two isomeric enolate anions. Under kinetic conditions, deprotonation at the least substituted carbon atom is favoured and the enolate anion with the least substituted double bond is in excess. Under thermodynamic conditions however, equilibration between the two enolate anions occurs and the enolate anion with the more substituted double bond eventually predominates. 

Addition of a silylating reagent such as Me3SiCl to the reaction mixture traps the enolate anions and produces two silyl enol ethers in a ratio which reflects the ratio of the enolate anions. Thus if 2-methylcyclohexanone is added to the hindered base LDA at -78 °C and the mixture stirred for 1 hour at -78 °C and quenched with MeySiCl, then the major product is the silyl enol ether derived from the kinetic enolate. In contrast, heating 2-methylcyclohexanone, triethylamine, and Me3SiCl at 130 °C for 90 hours... 

The enolate anions are more reactive towards electrophiles when they are associated with non-coordinating quaternary ammonium cations than when they are associated with lithium cations. Thus, as illustrated in Equations Si3.4 and Si3.5, quaternary ammonium derivatives are preferred as counterions for kinetic enolates in order to prevent any isomerization to the thermodynamic enolate occurring before reaction with the added electrophile proceeds. 

Most likely, kinetic control in the displacement of bromide by the intermediate enolate anion accounts for the observed diastereoselectivity. 

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