Nucleophiles, ambident enolate anions

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. 

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). 

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). 

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. 

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. 

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... 

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 . 

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. 

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. 

There are other paths that fit the medium, sources and sinks protonation of an anion, p.t., and addition to a polarized multiple bond by the oxygen of the enolate by AdgS or AdN2. There are two sites that can serve as a base or as a nucleophile on this ambident allylic source. We have three choices to evaluate proton transfer to oxygen,... 

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. 

Phenols can be viewed as stable forms of enol tautomers, and phenolate anions display ambident nucleophilicity at oxygen as weU as C2/C6 and C4 (ortholpara positions). Consequently, phenolate anions are susceptible to C—C bond formation upon reaction with appropriate organic electrophiles (e.g., alkyl halides and sulfonates). When bond formation occurs at a substituted arene carbon, a quatonaty centCT is generated, which may lead to isolation of stable cyclohexadienone products and complete a net alkylative dearomatization (Scheme 15.1) [2]. 

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... 

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