Alkylation, enolate ions nucleophilicity

Alkylation occurs by an 8 2 mechanism m which the enolate ion acts as a nucleophile toward the alkyl halide... 

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... 

Because they re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we ve already studied. For example, enolates react with primary alkyl halides in the SK2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C-C bond forms ... 

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. 

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. 

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. ... 

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. 

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... 

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. 

Baldwin concluded that the remarkable difference between these two cycliza-tions results from stereoelectronic control of the alkylation of the amhi-dent nucleophile, i.e. the enolate ion. For such an ion, carbon alkylation requires approach of the electrophile perpendicular to the plane of the enolate, whereas oxygen alkylation requires approach in the plane of the enolate. Consequently, in the five-membered ring case, the C-alkylation process 196A 198 (which can be considered as a 5-Endo-trigonal process) is sterically difficult, but not the 0-alkylation process 196B 197 (a 5-Exo-tetrahedral process). 

Platinacyclobutane complex 118 undergoes equilibrium heterolytic scission of the exocyclic carbon-carbon bond to form a cationic allyl complex and the organic enolate ion (Equation 35) <1993OM3019>. Similar dissociative ionization was previously reported for rearrangements of iridium and rhodium metallacyclobutane complexes formed by nucleophilic alkylation < 1990JA6420>. This carbon-carbon bond activation is generally associated with reversible central carbon alkylation of Jt-allyl complexes (Section 2.12.9.3.3), but the homolytic equivalent has recently been... 

Enolate ions can be alkylated with alkyl halides through the S 2 nucleophilic substitution of an alkyl halide ... 

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. 

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. 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

Q Show how enols, enolate ions, and enamines act as nucleophiles. Predict the products of their reactions with halogens, alkyl halides, and other electrophiles. Show how they are useful in synthesis. 

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. 

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. 

A stereoselective reaction leads to the exclusive or predominant formation of one of several possible stereoisomeric products. Thus, one reaction pathway from a given substrate is favored over the other (as in nucleophilic additions to cyclic ketones or alkylations of enolate ions). 

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