Ambident, enolate anions

The same behavior has been observed in the attack of electrophiles on the ambident enolate anions, of which many reactions are closely related to those of enamines [Eq. (2)] ... 

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. 

The base-catalysed rearrangements of cz-halo ketones are classical examples of the reactions of ambident enolate anions in solution. The extent of each of the two reactions shown in Equations [11] and [12] is principally a function of the type of solvent used. A protic solvent solvates more strongly at the oxygen centre of the ambident anion and thus reaction proceeds through the carbanion centre to yield the Favorskii species as the major product (Eqn [11]). In marked contrast, the Favorskii rearrangement does not occur in the gas phase. Here,... 

Enolate anions are ambident nucleophiles. Alkylation of an enolate can occur at either carbon or oxygen. Because most of the negative charge of an enolate is on the oxygen atom, it might be supposed that O-alkylation would dominate. A number of factors other than charge density affect the C/O-alkylation ratio, and it is normally possible to establish reaction conditions that favor alkylation on carbon. 

The two possible valence-bond structures of the enolate anion, 7a and 7b, show that the anion should act as an ambident nucleophile—a nucleophile with nucleophilic properties associated with both carbon and oxygen. The addition step in the aldol reaction therefore may be expected to take place in either of two ways The anion could attack as a carbon nucleophile to form a carbon-carbon bond, 8, leading ultimately to the aldol 9, or it might attack as an oxygen nucleophile to form a carbon-oxygen bond, thereby leading to the hemiacetal 10. By this reasoning, we should obtain a mixture of products 9 and 10. However, the aldol 9 is the only one of these two possible products that can be isolated ... 

However, since enolate anions are ambident nucleophiles with the distribution of charge between the a-carbon and oxygen conferring reactivity to both sites, alkylation may result at either site. 

However, a A H calculation usually predicts the C-reacted compound to be thermodynamically more stable than the Z-reacted compound (mainly because of the greater C-Z bond strength in the C-reacted product compared to the C=C in the Z-reacted). However, this does depend on the relative C-E vs. 0-E bond strength. It is important to determine which is the dominant effect, product formation based upon product thermodynamic stability or upon kinetic direction from HSAB theory. To do this we need to determine whether the reaction is under kinetic or thermodynamic control. Figure 9.1 gives a flowchart for the decision for a common ambident nucleophile, an enolate anion (Z equals oxygen). 

We need to record only that which has changed from our original observations. We now have a new source, the delocalized anion just formed. This enolate anion is nucleophihc on carbon 2, just what is needed for our addition process. Resonance forms indicate the ambident nature of the enolate, an allylic source ... 

Enolate anions present two possible sites for alkylation. Nucleophiles with more than one potential site for electrophilic attack are referred to as ambident nucleophiles. When the alkylating agent is an alkyl halide, carbon alkylation is normally... 

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. 

C-Silylation. 2-Silyloxazoles can be prepared by deprotonation and quenching the resulting ambident oxazole anion (isocyano enolate) chemoselectively with trialkylsilyl triflates (eq 46). Trialkylsilyl chlorides generally give the product of O-silylation. ... 

Enolate anions are ambident nucleophiles. Alkylation of an enolate anion may occur at either of two sites, carbon or oxygen. 

It might be supposed that this technique could be readily extended to alkylation of p-diketones, such as cyclohexane 1,3-dione, 17.34. These are certainly easy to deprotonate, but the alkylation reaction can present some problems (Figure 17.40). The extent of the 0-alkylation depends on the base used, the solvent (the alkoxide is naked in DMSO, but heavily solvated in methanol) and the electrophile. We describe enolate anions as ambident nucleophiles, since they can react either at carbon or oxygen. RO" is a hard nucleophile and reacts best with hard electrophiles such as... 

Other possible ambident nucleophiles include cyanii anion (CN ), methyl sulfinate anion (CH3SO2 ), ar acetone enolate (CH3COCH2 ). Identify the most electro rich atom(s) in each anion (based on charges alone), ar indicate the major product that should result from an S, reaction with methyl bromide at this atom(s). 

The reactions of nitroalkenes (42) with various enols (43b) (vinyl ethers, silyl, and acyl enolates, ketene acetals) have been studied in most detail (110, 111, 125—154). As a mle, these reactions proceed smoothly to give the corresponding nitronates (35f) in yields from high to moderate. As in the reactions with enamines, the formation of compounds (44b) is attributed to the ambident character of the anionic centers in zwitterionic intermediates analogous to those shown in Scheme 3.43. 

Anions derived from malonates are ambident nucleophiles, which can react at the carbon or oxygen atom. Therefore, carbon-carbon bond-forming reactions by alkylation or acylation of enolates have been encountered with difficulties. Side reactions which may cause problems are the above-mentioned competiting O-reaction and dialkylation . 

There is another correlation that seems to have validity in many situations, at least where kinetic control is dominant namely, the.freer (less associated) the ambident anion is from its cation, the more likely is the electrophile to attack the atom of the anion with the highest negative charge. Thus O-alkylation of the sodium enolate of 2-propanone is favored in aprotic solvents that are good at solvating cations [such as (CH3)2SO, Section 8-7F],... 

Methanol-0-4 methyl nitrite, and dimethyl disulfide have been examined as potential chemical probes for distinguishing between alkoxides and enolates in the gas phase.171 Methanol-0-d proved to be unsuitable and methyl nitrite reacts too slowly in contrast, the reactive ambident behaviour of dimethyl disulfide results in elimination across the C—S bond on reaction with alkoxides ( hard bases ) and attack at sulfur by enolates ( soft bases ). This probe has been applied to investigation of the anionic oxy-Cope rearrangement. The dianionic oxy-Cope rearrangement is a key step in a squarate ester cascade involving stereoinduced introduction of two alkenyllithium reagents cis to each other.172... 

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. 

To summarize, it can be stated that the freer the ambident anion in every respect, the larger the 0/C-alkylation ratio in the case of 1,3-dicarbonyl compounds [365]. Thus, if 0-alkylation products are desired in the alkylation of enolates, dipolar non-HBD and dissociating solvents such as A, A -dimethylformamide, dimethyl sulfoxide, or, especially, hexamethylphosphoric triamide should be used. If C-alkylation is desired, protic solvents like water, fluorinated alcohols, or, in the case of phenols, the parent phenol will be the best choice [365]. 

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