Ambident nucleophiles enolate ions

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. 

Enamines are ambident nucleophiles giving C- and N-alkylated products. Acceptable yields of C-alkylated products are obtained by using reactive alkyl halides such as CH3I, ally lie and benzylic halides, and a-halocarbonyl compounds. The resultant iminium ion intermediates no longer behave as a enolates, thus dialkylation is avoided. The stereochemical course of alkylation of the enamine derived from 2-methylcy-clohexanone is depicted below. The reason for the preferred parallel alkylation via a boat-like transition state over antiparallel alkylation via a chair-like transition state is the synaxial RX // CH3 interaction in the latter case. ... 

Enolate Ions. The most important ambident nucleophile is the enolate ion (34). Why does an enolate ion react with some electrophiles at carbon and... 

The resonance contributors of the enolate ion show that it has two electron-rich sites the a-carbon and the oxygen. The enolate ion is an example of an ambident nucleophile (ambi is Latin for both dent is Latin for teeth ). An ambident nucleophile is a nucleophile with two nucleophilic sites ( two teeth ). 

Second, and as discussed in Part A, Chapter 5, nucleophilicity in Sn2 reactions is associated with polarizability. The more easily a nucleophile s electronic cloud can be distorted to permit bond formation, the stronger an Sn2 nucleophile it will be. Comparison of the oxygen and carbon ends of an ambident enolate ion with regard to nucleophilicity leads to the conclusion that the less electronegative carbon atom is more polarizable and to the prediction that the carbon end of the anion will be more nucleophilic. 

Azlactone is commonly utilized as a precursor of a-quatemary a-amino acids and various heterocyclic compounds [28-30]. Because the enol form of azlactone has aromatic character, facile deprotonation from the C4-position affords the corresponding enolate under the influence of various bases. Interestingly, the enolate ion shows ambident reactivity and attacks the electrophile at either the C4-position (a-addition) or the C2-position (y-addition), thus acting as an a-amino enolate or an acyl anion equivalent, respectively (Fig. 1). The site-selectivity associated with this enolate seems to be heavily dependent on its stereoelectronic characteristics, and introduction of a bulky substituent into the Cl- or C4-position suppresses the nucleophilicity at the particular position. 

Each resonance form contributes to the characteristics of the enolate ion and thus to the chemistry of carbonyl compounds. The resonance hybrid possesses partial negative charges on both carbon and oxygen as a result, it is nucleophilic and may attack electrophiles at either position. A species that can react at two different sites to give two different products is called ambident ( two fanged from ambi, Latin, both dens, Latin, tooth). The enolate ion is thus an ambident anion. Its carbon atom is normally the site of reaction, undergoing... 

Since the carbanion-enolates are ambident ions with two different nucleophilic sites, they can be alkylated at C or at O. 

These results clearly show that the potential energy surface can contain a series of minima. The fact that selectivity in re-attack by the F ions can be observed indicates that the differences between the energy barriers for the secondary reactions control the distribution of the final products. The multistep character of these processes is further illustrated by the reactions observed when enolate anions are used as reactant ions. The ambident enolate anions may react with methyl pentafluorophenyl ether at the carbon or the oxygen site. If they react with the carbon site at the fluorine-bearing carbon atoms, then the molecule in the F ion/molecule complex formed contains relatively acidic hydrogen atoms so that proton transfer to the displaced F ion may occur. An example is given in (47) where the enolate anion, generated by HF loss, is not observed. An intramolecular nucleophilic aromatic substitution occurs instead and leads to a second F ion/ molecule complex. The F" ion in this complex then re-attacks the substituted benzofuran molecule formed, either by proton transfer or SN2 substitution. 

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. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

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