Alkylation, enolate ions substitution reactions

Diethyl propanedioate, commonly called diethyl malonate or malonic ester, is more acidic than monocarbonyl compounds pK =13) because its a hydrogens are flanked by two carbonyl groups. Thus, malonic ester is easih converted into its enolate ion by reaction with sodium ethoxide in ethanol. The enolate ion, in turn, is a good nucleophile that reacts rapidh with an alkyl halide to give an a-substituted malonic ester. Note in the following examples that the abbreviation "Et" is used for an ethyl group, CH2CH3. 

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. 

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. 

We have seen many reactions where nucleophiles attack unhindered alkyl halides and tosylates by the SN2 mechanism. An enolate ion can serve as the nucleophile, becoming alkylated in the process. Because the enolate has two nucleophilic sites (the oxygen and the a carbon), it can react at either of these sites. The reaction usually takes place primarily at the a carbon, forming a new C—C bond. In effect, this is a type of a substitution, with an alkyl group substituting for an a hydrogen. 

Enantioselective Alkylations and Catalytic Asymmetric Alkylations. a-Substitution of a carbonyl-containing substrate via generation of an enolate ion followed by subsequent reaction with an electrophile remains one of the most fundamental transformations in synthetic organic chemistry. A more recent advance to this type of transformation is the ability to perform this... 

Two of the four general carbonyl-group reactions—carbonyl condensations and a substitutions—take place under basic conditions and involve enolate ion intermediates. Since the experimental conditions for the two reactions are so similar, how can we predict which will occur in a given case When we generate an enolate ion with the intention of carrying out an < alkylation, how can we be sure that a carbonyl condensation reaction won t occur instead ... 

We call this disconnection enolate allylation because we want to alkylate an enolate ion with an allyl halide. We have already discussed (chapter 19) the regioselectivity problems inherent in reactions of allyl derivatives and you should recall that we want to react at the correct (less substituted) end of the allyl system and we want to make an f-alkcnc. The solution is to use a [3,3]-sigmatropic rearrangement. This is the reaction sequence ... 

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 leading to 2,2-dimethylcyclohexanone is the thermodynamic enolate ion because it is the more stable enolate ion since it has the more substituted double bond. (Alkyl substitution increases enolate ion stability for the same reason that it increases alkene stability Section 6.13.) Therefore, 2,2-dimethylcyclohexanone is the major product if the reaction is carried out under conditions that cause enolate ion formation to be reversible. 

If the electrophile is an alkyl halide, the enolate ion is alkylated. The less substituted a-carbon is alkylated when the reaction is under kinetic control, whereas the more substituted a-carbon is alkylated when the reaction is under thermodynamic control. 

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

Leaving group effects on the ratio of C- to O-alkylation can be correlated by reference to the hard-soft-acid-base (HSAB) rationale. Of the two nucleophilic sites in an enolate ion, oxygen is harder than carbon. Nucleophilic substitution reactions of the Sn2 type proceed best when the nucleophile and leaving group are either both hard or both soft. Consequently, ethyl iodide, with the very soft leaving... 

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