Kinetic control with enolate 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. 

Deprotonation of the ketone must be fast, complete, and irreversible for kinetic control of enolate formation. No equilibration of the enolates can be allowed to occur. Optimum conditions for kinetic control of deprotonation are Add the ketone slowly to an excess of very strong base (usually i-Pr2NLi, the anion of diisopropyl amine, p iabH = 36) in an aprotic solvent (such as dry tetrahydrofuran or dimethoxyethane). Since the A"eq for deprotonation of a ketone with this base is 10 = lO -, the reaction is... 

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). 

There is another correlation that seems to have validity in many situations, at least where kinetic control is dominant namely, the.freer (less associated) the ambident anion is from its cation, the more likely is the electrophile to attack the atom of the anion with the highest negative charge. Thus O-alkylation of the sodium enolate of 2-propanone is favored in aprotic solvents that are good at solvating cations [such as (CH3)2SO, Section 8-7F],... 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

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. 

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. ° ... 

Stork has demonstrated that, in analogy with enolate chemistry, deprotonation of a,3 unsaturated im-ines with butyllithium under kinetic control produces the cross-conjugated anion.Conversely, use of slightly less than 1 equiv. of lithium diisopropylamide leads ultimately (by equilibration) to the conjugated system (equation 47). 

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. 

As we saw in section 9.4.B,C, the reaction of an ester such as 623 with LDA, under kinetic control conditions, and subsequent reaction of the enolate anion (624) with chlorotrimethylsilane gives the silyl enol... 

CB1981] and the same reaction of the related silyl enol ether (16) using polymer supported mandelic acid leads to (5)-mandelic acid in up to 94% e.e. [94TL2891]. Low temperature protonation of the anion derived from (17) produces mainly the cis product by kinetic control [94CB1495] and hydroboration of (18) gives the cis hydroxymethyl compound with high... 

Enolate anions with extended conjugation can be formed by proton abstraction of a,p-unsaturated carbonyl compounds (1.9). Kinetically controlled alkylation of the delocalized anion takes place at the a-carbon atom to give the p,7-unsaturated compound directly. A similar course is followed in the kinetically controlled protonation of such anions. 

The enol acetate mixture can be analyzed by gas chromatography or by nmr analysis. Table 1.2 shows the data obtained for several ketones. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate, as is true in each of the cases shown in Table 1.2. The principal reason for this result is probably that removal of the less hindered hydrogen is more rapid, for steric reasons, than removal of more hindered protons, and this more rapid reaction leads to the less substituted enolate. Similar results were obtained when an amine anion, lithium diisopropylamide, was used instead of triphenylmethyllithium. On the other hand, at equilibrium it is the more substituted enolate that is usually the dominant species. The stability of carbon-carbon double bonds increases with increasing substitution, and it is this substituent effect that leads to the greater stability of the more substituted enolate. 

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. 

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