Alkylation, enolate ions Alkyl group

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

An alkylation reaction is used to introduce a methyl or primary alkyl group onto the a position of a ketone, ester, or nitrile by S 2 reaction of an enolate ion with an alkyl halide. Thus, we need to look at the target molecule and identify any methyl or primary alkyl groups attached to an a carbon. In the present instance, the target has an a methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane. 

The mechanism of these reactions is usually Sn2 with inversion taking place at a chiral RX, though there is strong evidence that an SET mechanism is involved in certain cases, ° especially where the nucleophile is an a-nitro carbanion and/or the substrate contains a nitro or cyano group. Tertiary alkyl groups can be introduced by an SnI mechanism if the ZCH2Z compound (not the enolate ion) is treated with a tertiary carbocation generated in situ from an alcohol or alkyl halide and BF3 or AlCla, or with a tertiary alkyl perchlorate. ... 

DMSO and /V, A- dime th y I fo nn a in i d c (DMF) are particularly effective in enhancing the reactivity of enolate ions, as Table 1.2 shows. Both of these compounds belong to the polar aprotic class of solvents. Other members of this class that are used as solvents in reactions between carbanions and alkyl halides include N-mcthyI pyrro I i donc (NMP) and hexamethylphosphoric triamide (HMPA). Polar aprotic solvents, as their name implies, are materials which have high dielectric constants but which lack hydroxyl groups or other... 

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... 

An unsuccessful attempt has been made to determine the separate electronic and steric effects of alkyl groups on the acidities of hydrocarbons, acetophenone derivatives, and acetone derivatives CH3COCHR1R2 (at either site) by multivariational analyses of experimental and theoretical acidities for each set.15 A thermodynamic cycle has been used to estimate the aqueous phase p/C, = 22.7 1.0 for the methyl group of acetic acid and p/C, = 3.3 1.0 for the corresponding enol.16 Equilibrium acidities have been determined for several nitroaryl substituted nitroalkanes and cyanomethanes, 2,4,6-TNT, and 9-cyanofluorene17 in acetonitrile the influence of common cation BH+ on the electronic spectra of the anions obtained in the presence of strong guanidine bases (B) has been attributed to formation of two types of ion pair.18... 

Enone 113 can adopt two different conformations 116 and 117. Attack on the top face of the most stable conformation 116 gives the chair-like enolate ion 1 8 while an attack from below the plane of the molecule yields the boat-like enolate ion 119. On the other hand, an attack on the bottom face of the less stable conformation 117 gives the chair-like intermediate 120 while that on the top face gives the boat-like intermediate 22K The formation of the boat-like 121 where the two groups (R and Y) are cis can be readily eliminated. The chair-like 118 which leads to the cis isomer has to compete with the boat-like 119 and the chair-like 120 which lead to the trans isomer. The possibility of steric hindrance between the incoming nucleophile and the alkyl group at C-4 exists only in the formation of 118. Therefore, this extra steric factor would disfavor the formation of the cis isomer. 

When an enolate ion is treated with an alkyl halide it results in a reaction called alkylation (Fig.E). The overall reaction involves the replacement of an a-proton with an alkyl group. The nucleophilic and electrophilic centres of the enolate ion and methyl iodide are shown (Fig.F). The enolate ion has its negative charge shared between the oxygen atom and the carbon atom because of resonance and so both of these atoms are nucleophilic centres. Iodomethane has a polar C—I bond where the iodine is a weak nucleophilic centre and the carbon is a good electrophilic centre. 

The a-protons of a ketone like propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion needed for the alkylation. An alternative method of preparing the same product by using a milder base is to start with ethyl acetoacetate (a [3-keto ester) (Fig.G). The a-protons in this structure are more acidic because they are flanked by two carbonyl groups. Thus, the enolate can be formed using a weaker base like sodium ethoxide. Once the... 

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

In both the acetoacetic ester synthesis and the malonic ester synthesis, it is possible to add two different alkyl groups to the a-carbon in sequential steps. First the enolate ion is generated by reaction with sodium ethoxide and alkylated. Then the enolate ion of the alkylated product is generated by reaction with a second equivalent of sodium ethoxide, and that anion is alkylated with another alkyl halide. An example is provided by the following equation ... 

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. 

The most reliable method for making the enone is to alkylate the Mannich base with Mel and then treat the ammonium salt with base. Enolate ion formation leads to an ElcB reaction rather like the dehydration of aldols, but with a better leaving group. 

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