Nucleophile hard versus soft

Regioselective addition to a,p-unsaturated carbonyl compounds is an age-old pursuit, and reactions selective for either 1,2- or 1,4-addition are ubiquitous in modern organic synthesis. Nucleophile character (hard versus soft) and solvent polarity (contact versus separated ion pairs),among other factors, contribute to the reaction outcome. The typical reaction of Grignard reagents with enones results in mixtures of 1,2- and 1,4-addition products. From their earliest inception, Cu(i) catalysts and reactants have been used to effect selective 1,4-addition in this archetypical transformation of organocuprates. ... 

Reactions of carbocations with free CN- occur preferentially at carbon, and not nitrogen as predicted by the principle of hard and soft acids and bases.69 Isocyano compounds (N-attack) are only formed with highly reactive carbocations where the reaction with cyanide occurs without an activation barrier because the diffusion limit has been reached. A study with the nitrite nucleophile led to a similar observation.70 This led to a conclusion that the ambident reactivity of nitrite in terms of charge control versus orbital control needs revision. In particular, it is proposed that SNl-type reactions of carbocations with nitrite only give kinetically controlled products when these reactions proceed without activation energy (i.e. are diffusion controlled). Activation controlled combinations are reversible and result in the thermodynamically more stable product. The kinetics of the reactions of benzhydrylium ions with alkoxides dissolved in the corresponding alcohols were determined.71 The order of nucleophilicities (OH- MeO- < EtO- < n-PrCT < / -PrO ) shows that alkoxides differ in reactivity only moderately, but are considerably more nucleophilic than hydroxide. 

We can also rationalize selectivity for elimination versus substitution, or attack of H versus attack on C in terms of hard and soft electrophiles (pp. 237-238). in an Sn2 substitution, the carbon centre is a soft electrophile—it is essentially uncharged, and with leaving groups such as halide the C-X a is a relatively low-energy LUMO. Substitution is therefore favoured by nucleophiles whose... 

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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