Enolates composition

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

The composition of the enol ethers trimethylsilyl prepared from an enolate mixture reflects the enolate composition. If the enolate formation can be done with high regio-selection, the corresponding trimethylsilyl enol ether can be obtained in high purity. If not, the silyl enol ether mixture must be separated. Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl... 

The effect of HMPA on the reactivity of cyclopentanone enolate has been examined.44 This enolate is primarily a dimer, even in the presence of excess HMPA, but the reactivity increases by a factor of 7500 for a tenfold excess of HMPA at -50° C. The kinetics of the reaction with CH3I are consistent with the dimer being the active nucleophile. It should be kept in mind that the reactivity of regio- and stereoisomeric enolates may be different and the alkylation product ratio may not reflect the enolate composition. This issue was studied with 2-heptanone.45 Although kinetic deprotonation in THF favors the 1-enolate, a nearly equal mixture of C(l) and C(3) alkylation was observed. The inclusion of HMPA improved the C(l) selectivity to 11 1 and also markedly accelerated the rate of the reaction. These results are presumably due to increased reactivity and less competition from enolate isomerization in the presence of HMPA. 

The first element of stereocontrol in aldol addition reactions of ketone enolates is the enolate structure. Most enolates can exist as two stereoisomers. In Section 1.1.2, we discussed the factors that influence enolate composition. The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer.5 When it reacts with benzaldehyde only the syn aldol is formed.4 The product stereochemistry is correctly predicted if the TS has a conformation with the phenyl substituent in an equatorial position. 

Other changes in deprotonation conditions can influence enolate composition. Relatively weakly basic lithium anilides, specifically lithium 2,4,6-trichloroanilide and lithium diphenylamide, give high Z E ratios.10 Lithio l,l,3,3-tetramethyl-l,3-diphenyldisilylamide is also reported to favor the Z-enolate.11 On the other hand, lithium IV-trimethylsilyl-wo-propylamide and lithium iV-trimethylsilyl-fert-butylamide give selectivity for the fi-enolate12 (see Scheme 1.1). 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The effectiveness of magnesium enolates as nucleophilic agents limits the interest of the reaction. With less substituted substrates (R = H), the aldol reaction is faster than the sily-lation. Moreover, due to solubility limitations, the authors are unable to determine whether the high thermodynamic kinetic ratio of silylenol ethers obtained accurately represents the magnesium enolate composition. Nonetheless, this method is an excellent procedure to selectively prepare the thermodynamic silylenol ether from an unsymmetrical ketone. ... 

Our decision also obviates consideration of the additional structural ambiguity arising from the temperature, phase and solvent dependence of the keto vs enol composition of the tautomeric mixture. 

The reversible dependence of the keto/enol composition on temperature (e.g. equation 14-52) establishes that the two forms are in equilibrium. This structural mobility renders the reactions independent of the proportion of enol and keto form, and it is convenient to treat the compounds here together with the alkoxides, irrespective of the precise composition of the isomeric mixture. 

The synthetic importance of the EDA and LiHMDS type of deprotonation has led to studies of enolate composition under various conditions. Deprotonation of 2-pentanone was examined with EDA in THE, with and without HMPA. C(l)-deprotonation was favored under both conditions, but the Z E ratio for C(3) deprotonation was sensitive to the presence of HMPA (0.75 M). More Z-enolate is formed when HMPA is present. 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative, and irreversible, This ideal is approached experimentally by using a very strong base such as lithium diisopropylamide or hexamethyldisilylamide in an aprotic solvent in the absence of excess ketone. Lithium as the counterion is better than sodium or potassium for regioselective generation of the kinetic enolate. Aprotic solvents are required because protic solvents permit enolate equilibration by allowing reversible protonation-deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration. 

The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of the more substituted enolate, and as illustrated... 

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