Thermodynamic control with enolate anions

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

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. 

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. 

The anionic inverse electron-demand 1,3-dipolar cycloaddition of nitrones 95 with lithium ynolates (equation 41) proceeds at 0°C to afford the substituted isoxazolidinones 97. The relative configuration is determined during the protonation step of the initial isoxazolidinone enolate adduct 96. With a thermodynamically controlled protonation, the trans products are mainly produced. The in situ alkylation of the resulting enolate adduct 96 furnishes the trisubstituted isoxazolidinone 98 with high diastereoselectivity. The isoxazolidinones are easily converted into /3-amino acids (99, 100) in good yield . 

Prolonged treatment with a strong base e.g. potassium tert-butoxide in tert-butanol) has the effect of permitting equilibration of the end anions, so that the A > -enolate becomes the main product under thermodynamic control. This is apparent in the methylation of the enolate anion at C(4) (see p. 168). Under acidic conditions equilibration proceeds much more rapidly, and acid catalysed substitution via enols occurs almost entirely at C(6) the transient intervention of a small proportion of the A -enol under acidic conditions was detected only by short-term deuterium-exchange experiments [no]. 

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... 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

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. 

Another example illustrates some the problems inherent in the intramolecular reaction that do not arise with the intermolecular version. Deprotonation of 151 with sodium ethoxide under thermodynamic control conditions gives enolate anion 152 and isolated product 156 (water was lost from the initial aldol product), which... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

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... 

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. 

For the condensation reaction of 60, 66, and 71, the thermodynamic reaction conditions constitute the traditional method of doing a Claisen condensation. This reaction may be modified to use kinetic control conditions using LDA as a base and THF as the solvent. An example is the reaction of 74 with LDA to form the ester enolate. Under these kinetic control conditions, assume that is large and that the reaction will give primarily the enolate anion such that... 

In one experiment using LDA (30), 2-benzylcyclohexanone (104) was converted to the enolate anion under kinetic conditions (the solvent is dimethoxy-ethane, which is abbreviated DME), and subsequent reaction with iodomethane gave a 73% yield of 105 (via alkylation of the kinetic enolate anion) and 6% of 106 (via the thermodynamic enolate anion). This example illustrates a typical alkylation reaction as well as a typical result of enolate anion chemistry under kinetic control conditions (Section 22.4.2). The main point is that an enolate anion is a carbon nucleophile and reacts with primary and secondary alkyl halides by what is a normal 8 2 pathway. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. 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 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form p-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes 56,57,84,99,100,102,108,110,114,115. Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product 52, 53, 54, 55, 59, 68, 69,98,99,101,125. 

The reaction of 2-butanone with LiNMeg in THF at -100°C generates the enolate anion in 10 minutes. Identify the reaction conditions as kinetic or thermodynamic control and briefly discuss how each reactant and reaction condition influences this. 

One possible reaction for 60 is an intramolecular condensation with the other carbonyl (see Chapter 22, Section 22.6, for reactions of this type), but that would lead to a four-membered ring product, 61. The activation barrier to form this strained ring is high, so this reaction is slow (see Chapter 8, Section 8.5.3). The reaction conditions favor thermodynamic control (protic solvent, hydroxide, heat see Chapter 22, Section 22.4.2), which means that enolate anion 60 is in equilibrium with the neutral diketone. Further reaction with hydroxide generates the kinetic enolate anion 62 as part of the equilibrium mixture. If 62 attacks the carbonyl in an intramolecular aldol reaction (Chapter 22, Section 22.6), a six-membered ring is formed (63) in a rapid and highly favorable process. 

Besides its use as a mechanistic probe, deuteriation of anions under kinetically controlled conditions is a potentially promising way to access deuteriated molecules in a regio- and stereo- controlled manner, in opposition to the thermodynamic equilibration in the presence of an excess of deuterium donor. Thus, treatment of the lithium anion of 2-methyltetralone (p E = 7.31, pfsfEa = 10.8, pKkr = 18.1 in water)335, by one equivalent of a solution of deuterium chloride in deuterium oxide, generates the intermediate O-deuteriated enol whose reaction with water or with an excess of deuterium chloride in deuterium oxide conducts to, respectively, the tetralone or the deuteriated tetralone (Scheme 69)336. 

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. ... 

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