Alkylation, enolate ions strong bases

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

As in 0-94, the alkyl halide may be primary or secondary, Tertiary halides give elimination. Even primary and secondary halides give predominant elimination if the enolate ion is a strong enough base (e.g., the enolate ion from Me3CCOMe).146,1 Tertiary alkyl groups, as... 

Enolate ions, which are usually strong nucleophiles, are more important in preparative applications than are the enols. In additions to carbonyl groups, the carbon end, rather than the oxygen end, attacks but in SA,2 substitutions on alkyl halides, significant amounts of O-alkylation occur. The more acidic compounds, such as those with the j3-dicarbonyl structure, yield enolates with the greater tendency toward O-alkylation. Protic solvents and small cations favor C-alkylation, because the harder oxygen base of the enolate coordinates more strongly than does the carbon with these hard Lewis acids.147... 

The enolate ions of esters or ketones can also be alkylated with alkyl halides to create larger carbon skeletons [Following fig.(b)]. The most successful nucleophilic substitutions are with primary alkyl halides. With secondary and tertiary alkyl halides, the elimination reaction may compete, particularly when the nucleophile is a strong base. The substitution of tertiary alkyl halides is best done in a protic solvent with weakly basic nucleophiles. However, yields may be poor. 

Therefore, diethyl malonate is deprotonated but not ethyl acetate. Moreover, the ethoxide ion is strong enough to deprotonate the diethyl malonate quantitatively such that all the diethyl malonate is converted to the enolate ion. This avoids the possibility of any competing Claisen reaction since that reaction needs the presence of unaltered ester. Diethyl malonate can be converted quantitatively to its enolate with ethoxide ion, alkylated with an alkyl halide, treated with another equivalent of base, then alkylated with a second different alkyl halide (Fig.R). Subsequent hydrolysis and decarboxylation of the diethyl ester yields the carboxylic acid. The decarboxylation mechanism (Fig.S) is dependent on the presence of the other carbonyl group at the P-position. 

In the presence of a very strong base, such as amide ion or an organolithium reagent, it is possible to convert dicarbonyl compounds to their dianions. Subsequent alkylation of such dianions leads to alkylation at the more strongly basic enolate site, rather than at the carbon atom between the two carbonyl carbons. The more acidic methylene group activated by two carbonyl substituents is the preferred site in the monoanion, as discussed earlier. The ability to determine the site of monoalkylation by choice of the amount and nature of the basic catalyst has significantly expanded the synthetic utility of enolate alkylations. Scheme 1.7 gives some examples of formation and alkylation of dianions. 

The nitrogen analogs of enolate ions can be prepared from imines and strong bases. The resulting anions are alkylated by alkyl halides ... 

Stork and Ponaras have developed a method, involving the intermediacy of P-hydroxyhydrazones, for the introduction of alkyl and aryl groups on the a-carbon of an aP-unsaturated ketone, based on principles discussed previously. The method is particularly useful in situations where the thermodynamic enolate ion (y-carbon) cannot, or must not for the sake of other sensitive groups, be formed. Acid-catalysed dehydration of substituted cyclohex-3-ene-l,2-diols, readily formed from dienone precursors, yielded mixtures of cyclohex-2-enones and substituted benzenes. The product ratio was strongly dependent on reaction conditions and on the substituent group at C-1, but independent of the initial diol configuration, thus indicating a common cationic intermediate. Conditions were found which allow the synthetic use of the transformation sequence shown (Scheme 2) in up to 90 % yield. 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

It is important that a strong base such as LDA is used to form the enolate ion. If a weaker base such as hydroxide ion or an alkoxide ion is used, very little of the desired monoalkylated product will be obtained. We have seen that these weaker bases form only a small amount of enolate ion at equilibrium (Section 18.6). Therefore, after monoalkylation has occurred, there is still a lot of base present in solution, which can form an enolate ion from the monoalkyated ketone as well as from the unalkylated ketone. As a result, di-, tri-, and even tetra-alkylated products may be produced. 

In practice, the strong base lithium diisopropylamide [LiN(i-C3H7)2 abbreviated LDA] is commonly used for making enolate ions. As the lithium salt of the weak acid diisopropylamine, pl a = 36, LDA can readily deprotonate most carbonyl compounds. It is easily prepared by reaction of butyllithium with diisopropylamine and is soluble in organic solvents because of its two alkyl groups. 

In practice, however, the reaction may be complicated by several factors. The enolate ion is a fairly strong base. Therefore, alkylation is normally feasible using only halomethanes... 

In some respects, the alkylation of enolate anions resembles nucleophilic substitution. We recall that many nucleophiles displace leaving groups from primary alkyl halides by an Sj 2 mechanism (Section 9.3). A similar reaction occurs with secondary alkyl halides, but competing elimination reactions also occur. Primary alkyl halides react with carbanions, such as the alkynide ion, by an Sj 2 mechanism. (Secondary alkyl halides react not only in displacement reactions but also in elimination reactions because the alkynide ion is a strong base.)... 

We also know that hydroxide ion or alkoxide ions are not basic enough to form the enolate ion in high concentration. Hence, the hydroxide ion or alkoxide ion would substitute for the halide ion of the alkyl halide to give an alcohol or ether. However, strong bases, such as potassium hydride or LDA, yield stoichiometric quantities of the enolate. An alkyl halide is then added to the solution of the enolate to give the a-alkylated product. 

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