Nucleophiles, ambident cyanide

The intermediacy of a carbocation or complex-equivalent is attractive, if one considers that the nucleophilic ambident cyanide ion may be accomodated on secondary or tertiary cationic sites. Where exceptions (e.g., 125,126,134-136 cf. Sect. 4.3) exist, the cationic intermediate resides on a primary allylic carbon. The following skeletal types are examples of some biogenetic schemes offered in conjunction with the structural determination of isocyanoterpenoids ... 

Other possible ambident nucleophiles include cyanide anion (CN ), methyl sulfinate anion (CH3S02 ), and acetone enolate (CH3COCH2 ). Identify the most electron-rich atom(s) in each anion (based on charges alone), and indicate the major product that should result from an SN2 reaction with methyl bromide at this atom(s). 

Since the cyanide anion is an ambident nucleophile, isonitriles R—NC may be obtained as by-products. The reaction pathway to either nitrile or isonitrile can be controlled by proper choice of the counter cation for the cyanide anion. 

The cyanide ion is an ambident nucleophile and isocyanides may be side products. If the preparation of isocyanides is desired, they can be made the main products by the use of silver or copper(I) cyanide (p. 459). Vinylic bromides can be converted to vinylic cyanides with CuCN, with KCN, a crown ether, and a... 

Another premise cannot be excluded and will be investigated eventually. As in the case of cyanide ion, isothiocyanate ion may be a precursor in the biosynthesis of some marine isothiocyanates. Like cyanide, thiocyanate ion is an ambident nucleophile. Specific incorporation of this ion by a carbocationic site... 

Cyanide is an ambident nucleophile, and can also react on nitrogen to yield isonitriles. 

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. 

Thiocyanate ions, cyanide ions and nitrite ions can each react with an electrophile R+, depending upon its nature and the conditions, to give either of two products a thiocyanate 4.24 or an isothiocyanate 4.25 from the thiocyanate ion, an isonitrile 4.26 or a nitrile 4.27 from cyanide ion, and an alkyl nitrite 4.28 or a nitroalkane 4.29 from nitrite ion. Each is nucleophilic at more than one site, and nucleophiles like these are called ambident. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

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. ... 

It should be mentioned briefly that solvation phenomena should also influence the outcome in the case of ambident nucleophiles, at least to the extent to which these reagents are sensitive to solvent effects. With an ambident anion, which is not manipulated by countercations (formation of ion pairs), the more electronegative center should attack preferentially. The more this area is blocked by hydrogen bridges formed in protic solvents, or shielded by countercations, the more likely it is that the less electronegative end will react. If dipolar aprotic solvents are used, which can only solvate the cations, a preferential attack of the nonshielded more electronegative center is to be expected. It must be realized, however, that in substitution reactions employing cyanide ions, dipolar aprotic solvents have not been reported to enhance the formation of isonitriles. " ... 

Treatment of alkylating agents with metal cyanides should in principle be the method of choice for preparing isocyanides (equation 25). But as the cyanide ion again represents an ambident nucleophile, the well-known problems already discussed will arise (Section 1.8.2.1.i). It remains to be stated that simple alkylation of alkali metal cyanides with halogen compounds or dialkyl sulfates is not useful for the preparation of isonitriles. The formation of nitriles always prevails and isocyanides are at best obtained in yields of up to 25%. " The prospects are much tetter in the alkylation of heavy metal cyanides, if the reaction is done under conditions which initially give rise to isocyanide-transition metal complexes (equation 26). These will then be transformed into isonitriles by treatment with KCN. Under optimized conditions this technique yielded 55% of ethyl isocyanide. ... 

The thiocyanate, cyanide, and nitrite ions are also ambident nucleophiles. The thiocyanate ion is softer on the sulfur atom and harder on the nitrogen atom. Likewise, the cyanide ion is softer on the carbon atom and harder on the nitrogen atom, and the nitrite ion is harder on the oxygen atom and softer on the nitrogen atom. Depending on the nature of the electrophile R+ and also the reaction conditions, each of these ions can react to give either of the two possible products the thiocyanate 74 or the isothiocyanate 75 from the thiocyanate ion 73, the nitrile 77 or the isonitrile 78 from the cyanide ion 76, and the nitroalkane 80 or the alkyl nitrite 81 from the nitrite ion 79. 

The cyanide ion has two nucleophilic atoms it is what is called an ambident nucleophile. 

A -AIkyl-2-azidobenzothiazolium tetrafluoroborates exhibit ambident reactivity with nucleophiles. With hard nucleophiles, e.g. hydroxide ion, methoxide ion, or dimethylamine, reaction occurs at the 2-position with displacement of azide ion. In contrast, softer nucleophiles, e.g. azide ion, cyanide ion, toluene-p-... 

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