Enolate ions soft nucleophile

However, if we look at the LUMO, we find that it has the form 4.65, namely that of ift4 of benzene, but polarised by the nitrogen atom. This polarisation has reduced the coefficient at C-3, and the coefficient at C-4 is larger than that at C-2, as can be seen from the simple Hiickel calculation for pyridine itself in Fig. 4.11, which gives LUMO coefficients of 0.454 and —0.383, respectively, and an energy of 0.56/3 (compare benzene with 1/3 for this orbital). Thus, soft nucleophiles should attack at C-4, where the frontier orbital term is largest. Again this is the case cyanide ion, bisulfite, enolate ions, and hydride delivered from the carbon atom of the Hantsch ester 4.67 react faster at this site. 

Moving to a,/3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.77 by direct attack at the carbonyl group to give ester hydrolysis and exchange, respectively, whereas the /3-dicar-bonyl enolate ion 4.78 (a soft nucleophile) undergoes a Michael reaction. There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group is not a more rapid (and reversible) process. 

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. 

Hydroxide and alkoxide ions, both hard nucleophiles, react with ethyl acrylate 93, an a,p-unsaturated ester, by direct attack at the carbonyl carbon to bring about ester hydrolysis and ester exchange, respectively. However, the enolate 94, a soft nucleophile, reacts in conjugate manner to form 95 predominantly. In an alternate pathway, it is also likely that the enolate 94 reacts through the oxy anion (hard nucleophile) directiy at the carbonyl carbon (hard electrophile) to generate the species 96, which rearranges in an oxy anion accelerated [3.3] sigmatropic shift manner, as shown, to form 97 and, thus, the above product 95. However, it is not certain that such a direct attack by the enolate is not more rapid and reversible. 

Now Sn2 opening of the protonated lactone with the soft nucleophile (bromide ion) gives the y-bromoketone that cyclizes through its enolate. The formation of three-membered rings is favoured kinetically. 

Secondly, as Professor House discussed in his book and papers, the importance of the nature of intermediary metal enolate in the acylation reaction should be taken into consideration. Thus the procedure for the preferable formation of a contact ion pair type of metal enolate by adding magnesium salt to the lithiated solution should be preferred for the acylation on carbon over oxygen. Thirdly, recent introduction of cyanoformate as soft electrophile would be preferable because C-16 plays as soft nucleophile while oxygen of carbonyl group as hard nucleophile. 

The first formed enolate ion is an example of a soft nucleophile (Section 8.5.4)... 

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... 

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). 

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