Alkylation, enolate ions structures

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 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... 

Under the conditions of most alkylation reactions, the products of O- and C-alkylation are usually not interconvertible, so it is not valid to predict C-alkylation directly on the basis of thermodynamic considerations. But, the transition state B and D resemble the products C and E, respectively, to a significant extent. It is therefore expected that the transition state for C-alkylation will be lower in energy, anticipating to some extent the greater stability of the product. This is depicted in Figure 1.2. The competition between O- and C-alkylation will then depend upon the interplay among (1) solvation effects, (2) nucleophilicity of the C and O ends of the enolate ion, and (3) transition-state structure. 

The proportion of the /rans-O-alkylated product [101] increases in the order no ligand < 18-crown-6 < [2.2.2]-cryptand. This difference was attributed to the fact that the enolate anion in a crown-ether complex is still capable of interacting with the cation, which stabilizes conformation [96]. For the cryptate, however, cation-anion interactions are less likely and electrostatic repulsion will force the anion to adopt conformation [99], which is the same as that of the free anion in DMSO. This explanation was substantiated by the fact that the anion was found to have structure [96] in the solid state of the potassium acetoacetate complex of 18-crown-6 (Cambillau et al., 1978). Using 23Na NMR, Cornelis et al. (1978) have recently concluded that the active nucleophilic species is the ion pair formed between 18-crown-6 and sodium ethyl acetoacetate, in which Na+ is co-ordinated to both the anion and the ligand. 

Alkylation Alkylation of the phenylindanone 31 with catalyst 3a by the Merck group demonstrates the reward that can accompany a careful and systematic study of a particular phase-transfer reaction (Scheme 10.3) [5d,5f,9,36], The numerous reaction variables were optimized and the kinetics and mechanism of the reaction were studied in detail. It has been proposed that the chiral induction step involves an ion-pair in which the enolate anion fits on top of the catalyst and is positioned by electrostatic and hydrogen-bonding effects as well as 71—71 stacking interactions between the aromatic rings in the catalyst and the enolate. The electrophile then preferentially approaches the ion-pair from the top (front) face, because the catalyst effectively shields the bottom-face approach. A crystal structure of the catalyst as well as calculations of the catalyst-enolate complex support this interpretation [9a,91]. Alkylations of related active methine compounds, such as 33 to 34 (Scheme 10.3), have also appeared [10,11]. 

Treatment with base (usually LDA) at low temperature produces an enolate, and you can clearly see that the auxiliary has been designed to favour attack by electrophiles on only one face of that enolate. Notice too that the bulky auxiliary means that only the Z-enolate forms alkylation of the E-eno-late on the top face would give the diaster eoisomeric product. Coordination of the lithium ion to the other carbonyl oxygen makes the whole structure rigid, fixing the isopropyl group where it can provide maximum hindrance to attack on the wrong5 face. 

---