Enolate anions, kinetic thermodynamic

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. 

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). 

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. 

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. 

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). 

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... 

If an unsymmetrical ketone is used in this reaction, the problem is exacerbated. Reaction of 42 with sodium ethoxide, under thermodynamic control conditions, generates two different enolate anions. When reacted with an aldehyde with no a-hydrogens (benzaldehyde), two aldol products are formed (131 and 132). When 42 reacts with sodium ethoxide under thermodynamic conditions in the presence of an unsymmetrical ketone such as 2-butanone, the kinetic and thermodynamic enolates of both ketones are formed, which means that four different enolate anions are formed, and each one reacts with two different ketones. Therefore, the attempted mixed aldol condensation of 2-butanone and 42, therefore, produces eight different aldol products. 

The intermediate AD is a 1,5-diketone and as such accessible by means of a Michael addition of D (as an enolate anion) to A (in a yield of 52%). It is a characteristic of the photochemical synthesis of 123b that the kinetical-ly favored cw-orientation of the ethyl and vinyl groups on the five-membered ring of the Michael adduct AD ensures the thermodynamically disfavored fran -fusion of rings C and D in the Diels-Alder adduct of type ABCD. The overall yield of 123b, based on D, amounts to 11% ). The achiral building block A is accessible by conventional means [118d]. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

Directed aldol reaction (Section 19.5B) A crossed aldol reaction in which the desired enolate anion is generated first and rapidly using a strong base (e.g., LDA) after which the carbonyl reactant to be attacked by the enolate is added. If both a kinetic enolate anion and a thermodynamic enolate anion are possible, this process favors generation of the kinetic enolate anion. 

Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions. 

If ethanol is the solvent, there is a problem. Ethanol has a pKg of about 15.9 and it is clearly much more acidic than 2-butanone. Once formed, the enolate anion (also a strong base) will react with ethanol to give 2-butanone as the conjugate acid. In other words, in the protic solvent, 34 will react with ethanol to regenerate 32, and this reaction shifts the equilibrium back to the left (Kgi is small), which favors the thermodynamic process. Therefore, an aprotic solvent will favor a large and kinetic control whereas a protic solvent will favor a small and thermodynamic control. 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

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