Hard-soft, acid-bases ambident nucleophiles

The properties of dimethyl carbonate, (MeO)2CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard-soft character. Results were in good agreement with the Hard-Soft Acid-Base theory, hard nucleophiles attacking the hard C=0 group and soft nucleophiles the soft Me group (Scheme ll).37... 

A detailed examination of the reactions of ambident nucleophiles has shown that hard-soft acid-base theory and the Klopman-Salem model based on charge- and orbital-control of a reaction are not able to predict the results found in many reactions involving ambident nucleophiles. The analysis of the reactions of many ambident nucleophiles with a variety of substrates indicates that Marcus theory, which derives... 

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. 

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. 

As cyanide ions operate as ambident nucleophiles, alkylation reactions may generate isonitriles as well as nitriles (equation 2). A whole range of parameters is responsible for the outcome of reactions of this type and their particular role together with special counter influences is not easily evaluated. There is a large and growing number of papers on this topic, but one can concentrate here on a few selected review articles.Suffice it to say that Komblum s seminal article s from 1955 is still of special importance in this field. Pearson s principle of soft and hard acids and bases (HSAB) proved to be particularly helpful in the interpretation of experimental results. ... 

In other words, it is sometimes nucleophilic on carbon and sometimes on nitrogen nucleophiles like this are called ambident. The principle of hard and soft acids and bases helps us to classify and remember this pattern of reactivity. It tells us that the carbon atom will be the softer and the nitrogen atom the harder end of the nucleophile (since, other things being equal, as we have seen in the last section, hard nucleophiles are on the right in the periodic table). 

Nucleophiles with two sites that could react with electrophiles are called ambident nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the softer nucleophilic site. For instance, the sulfenate ion 70 is an ambident nucleophile, because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen atom, where most of the negative charge is concentrated, to give the sulfenate ester 71 and (b) with methyl iodide, a soft electrophile, to give the sulfoxide 72. Sulfur atom is the softer of the two nucleophilic sites available in the sulfenate ion and, furthermore, it is rendered more nucleophilic by the a-effect arising from the adjacent oxygen atom. 

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