Hard electrophiles reaction with enolate

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

A wasteful side reaction which sometimes occurs in the alkylation of 1,3-dicarbonyl compounds is the formation of the 0-alkylated product. For example, reaction of the sodium salt of cyclohexan-l,3-dione with butyl bromide gives the 0-alkylated product (37%) and only 15 % of the C-alkylated 2-butylcyclohexan-1,3-dione. In general, however, 0-alkylation competes significantly with C-alkylation only with reactive methylene compounds in which the equilibrium concentration of enol is relatively high (as in 1,3-dicarbonyl compounds). The extent of C- versus 0-alkylation for a particular 1,3-dicarbonyl compound depends on the choice of cation, solvent and electrophile. Cations (such as Li+) that are more covalently bound to the enolate oxygen atom or soft electrophiles (such as alkyl halides) favour C-alkylation, whereas cations such as K+ or hard electrophiles (such as alkyl sulfonates) favour 0-alkylation. 

It might be supposed that this technique could be readily extended to alkylation of p-diketones, such as cyclohexane 1,3-dione, 17.34. These are certainly easy to deprotonate, but the alkylation reaction can present some problems (Figure 17.40). The extent of the 0-alkylation depends on the base used, the solvent (the alkoxide is naked in DMSO, but heavily solvated in methanol) and the electrophile. We describe enolate anions as ambident nucleophiles, since they can react either at carbon or oxygen. RO" is a hard nucleophile and reacts best with hard electrophiles such as... 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

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