Enolates sodium hydride

Any equilibrium will produce the thermodynamically most stable enolate. The most stable enolate will have the greatest charge delocalization. In the above example, the thermodynamically favored enolate is conjugated the kinetically favored enolate is not. Common conditions for thermodynamic control are to use average bases (like sodium ethoxide or potassium tert-butoxide, p abH 16 to 19) in alcohol solvents. Proton transfer equilibria rapidly occur among base, solvent, ketone, and enolate. Sodium hydride or potassium hydride in an ether solvent are also thermodynamic reaction conditions that allow equilibration between the ketone and the enolate. Enones have two possible enolates weaker bases give the thermodynamically more stable extended enolate, whereas kinetic conditions produce the cross-conjugated enolate. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The familiar alkylation of -ketoesters followed by decarboxylation is still a useful route to a-alkyl ketones, although the alkylation of enamines is frequently the preferred route. Given below are two examples of alkylation of 2-carbethoxycycloalkanones (prepared in Chapter 10, Section I). In the first case, sodium ethoxide is the base employed to generate the enolate ion of 2-carbethoxycyclohexanone. In the second case, the less acidic 2-carbethoxycyclooctanone requires sodium hydride for the generation of the enolate ion. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Tetraphenyl-3//-azepine (2) is formed by the action of sodium hydride on 1-benzyl-2,4,6-triphenylpyridinium tetrafluoroborate (1) in refluxing toluene.37 The 3//-azepine. which arises by attack of the carbanion, generated at the benzylic carbon, at the 2-position of the pyridine ring, is also formed, unexpectedly, in the reaction of the pyridinium tetrafluoroborate with the enolate of ethyl 2-methyl-3-oxobutanoate. 

Addition of the chelated enolate of the S-oxo ester moiety of a 2,8-dioxo-6-alkenoate 1 under thermodynamic control at 25 °C using stoichiometric or catalytic amounts of sodium hydride in benzene results in the formation of tram-2-oxo-5-(2-oxoalkyl)-l-cyclopentane-carboxylate 2 exclusively. 

Inclusion of basic nitrogen in the p-position is also compatible with antiinflammatory activity in this series. Nitration of phenylacetic acid (27) affords 28. Methyl iodide alkylation of the enolate prepared from 28 using two equivalents of sodium hydride gives 29. This appears to involve an Ivanov intermediate (28a). Catalytic reduction of the... 

A complementary method was reported 3 years later by Hino, in which a readily enolizable diketopiperazine 48 was directly converted to the epidisulfide by deprotonation with sodium hydride and exposure to sulfur monochloride [38]. As with the Trown method, this method was limited to a specific class of substrates, namely, ones possessing a 1,3-dicarbonyl motif at each of the reactive centers, yet it has also seen subsequent applications in total synthesis [39, 40]. In 1972, Schmidt was able to significantly broaden the scope of the enolate thiolation method by introducing elemental sulfur as the electrophilic agent [41]. In contrast to Hino s method in which formation of a highly reactive, unstable adduct requires readily... 

The enolate solution is added slowly with cooling and vigorous stirring so that the temperature of the reaction mixture remains below 30°. After all the supernatant enolate solution has been transferred, the residual slurry of sodium hydride is washed with an additional 50-ml. portion of anhydrous 1,2-dimethoxyethane (Note 3), and these washings are also added to the acetic anhydride solution. The resulting viscous mixture is stirred at room temperature for an additional 30 minutes and then poured cautiously into a mixture of 500 ml. of pentane, 500... 

When the carbonyl compound is added to this base, abstraction of a proton and formation of the enolate anion follow, as seen with sodinm hydride or sodium amide above. Again, this reaction is essentially irreversible because the other product is the weak base diisopropylamine (pATa 36). So far, there does not seem any particular advantage in nsing LDA rather than sodium hydride or sodium amide. 

Let US use a systematic approach to consider what product is most likely to result when a mixture of an ester and a ketone, both capable of forming enolate anions, is treated with base. For example, consider an ethyl acetate-acetone mixture treated with sodium hydride in ether solution. 

Very strong bases can be used in other reactions that are similar to the Claisen condensation. In these reactions, carbanions are formed instead of enolates. Figures 15-7, 15-8, and 15-9 show examples of various reactions employing three different strong bases sodium ethoxide, sodium amide, and sodium triphenylmethanide. Sodium hydride, NaH, is a strong base that would also work. Any of these very strong bases could be used in each of the specific reactions. 

Sodium hydride and potassium hydride can also be used to prepare enolates from ketones. The reactivity of the metal hydrides is somewhat dependent on the means of preparation and purification of the hydride.5... 

An interesting 1,2-induced diastereoselective allylation is that of 2-aryl-3-methylbutenolide 33 with allyl bromide24. This reaction is worth noting, in the sense that the enolate was formed with sodium hydride and the reaction temperature never went below 0°C, although the yield and diastereoselectivity were still very good, Although lactone 33 is a special case with its a-aryl substituent, it does seem that very low temperatures are not always really necessary. 

Enolate anions of esters, such as ethyl 3-oxobutanoate or diethyl propanedioate, react with aeyl halides or anhydrides to give acylation products. These reactions are carried out best using sodium hydride instead of sodium ethoxide for production of the enol salt, because then no alcohol is liberated to react with the acyl halide or anhydride ... 

The optimal reaction conditions for reactions involving catalyst 33 and substrates 16a-c or 34 were investigated, and it was found that best results were obtained at room temperature [36] with toluene as the solvent [37] and with sodium hydroxide or sodium hydride as the base. In particular, the use of potassium hydroxide always gave lower enantioselectivities than sodium hydroxide, and lithium hydroxide was not effective in these reactions. Attempts to use aqueous sodium hydroxide as the base under liquid-liquid phase-transfer conditions resulted in the formation of a negligible amount of product [33,34]. An important finding of these optimization studies was the presence of a significant background reaction [38], Hence, one role of catalyst 33 must be to enhance the reactivity of an enolate when it is coordinated to the catalyst relative to the uncoordinated enolate. 

---