Enolate anions, kinetic reactions

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. 

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. 

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). 

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. 

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]. 

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. 

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. 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

Knochel and Seebach similarly converted 239 to 242 by condensation with 241. The successful reaction of the thiol ester enolate anion of 239 with electrophiles seems to result from the higher kinetic acidity of the thiol ester as compared to the acidity of the normal ester . 

This compound has some similarities to the enol form of a carbonyl compound, and it is called an enamine. As this reaction is performed under reversible conditions, the thermodynamic isomer is always formed, i.e. the double bond is formed on the most highly substituted side. These compounds are of great synthetic importance. Furthermore, their use complements the use of the anions formed from carbonyl compounds. This is because enolate anions are usually produced under strongly basic, i.e. irreversible, conditions, and so the proton that is normally removed is the kinetically favoured one. Hence, the hydrogen atom that is removed in the formation of the enolate anion may be different from the one that is eliminated under thermodynamic conditions prevalent in the formation of the carbon/carbon double bond of the enamine. 

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). 

The high values of the pK s of carbon acid substrates and the associated instability of enolate anion intermediates in nonenzymatic reactions first led to the expectation that these intermediates could not be rendered kinetically competent in enzymatic reactions [3]. As a result, the expectation was that these reactions must be concerted, thereby avoiding the problem of how an active site might provide sufficient, significant stabilization of the intermediates. However, the weight of the experimental evidence now is that enzymes that abstract protons from carbon acids are able to sufficiently stabilize enolate anion intermediates so that they can be kinetically competent. 

X 10 if the enolate anion intermediate were not stabilized in the active site this value is 10 -fold less than the observed value for the kcat, 500 s. Recall that an enolate anion is necessarily on the reaction coordinate, so the value of AG° must be reduced for the enolate anion to be kinetically competent irrespective of whether AG int can be reduced. Thus, the active site of mandelate racemase must decrease AG° from the value predicted from the values of the substrate carbon acid and the active site base in solution. The obvious strategy to accomplish this reduction is preferential stabilization of the enolate anion intermediate relative to the carbon acid substrate, the increased negative charge on (or proton affinity of) the carbonyl/carboxylate oxygen of the enolate anion intermediate provides a convenient handle for enhanced electrostatic or hydrogen bonding interactions with the active site. 

Although not a subject of this chapter, Toney and coworkers have quantitated the reaction coordinate of a PLP-dependent L-alanrne racemase [15]. Despite the expectation that the cofactor provides resonance stabilization of the carbanion/enolate anion (quinonoid) intermediate derived by abstraction of the a-proton, the spectroscopic and kinetic analyses for the wild type racemase at steady-state provided no evidence for the intermediate in the reaction catalyzed by the wild type enzyme. Indeed, Toney had previously demonstrated that a kinetically competent quinonoid intermediate accumulates in the impaired R219E mutant [16] Arg 219 is hydrogen-bonded to the pyridine nitrogen of the cofactor. For the wild type racemase, the derived transition state energies for conversion of the bound enantiomers of alanine,... 

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... 

Generation of enol silyl ethers from acyclic ketone precursors can be accomplished using the same kind of reagents. Depending on the reaction conditions, stereoselective formation of either the ( )- or the (Z)-isomer of the enol silyl ethers has been reported (Scheme 11). An in situ method of generating the enolate anion with lithium dialkylamides in the presence of trimethylchlorosilane leads to enhanced selection for the kinetically preferred enol silyl ether (e.g. 34a). Lithium r-octyl-r-butylamide (LOBA) is... 

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