Enolates are Ambident Nucleophiles

Enolates can act either as carbon or as oxygen nucleophiles. The product depends on the electrophile e.g. 

Is the C product or O product more stable Can the experimental results be explained by thermodynamics  

Electrostatic interactions can guide alkylation under certain conditions. Examine the electrostatic potential map of the potassium enolate of ethyl acetoacetate. Is carbon or oxygen more electron rich Are electrostatic interactions likely to favor addition of oxygen or carbon Examine atomic charges and electrostatic potential maps for diethylsulfate, ethyl chloride, ethyl bromide and ethyl iodide, pay attention to the backside of the electrophilic carbon. Order the systems from most to least electron poor. Which reaction is most likely to be guided by electrostatics Least likely Can the experimental results be fully explained on this basis  

Electrostatic potential map of the potassium enolate of ethyl acetoacetate shows negatively-charged regions (in red) and positively-charged regions (in blue). 

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There can be a problem of 0 versus C alkylation (enolates are ambident nucleophiles). 

Enolates can be used as the leaving group (Scheme 9.57). If they are, then they will also become the nucleophile. Enolates are ambident nucleophiles and can be O- or C- alkylated. 0-alkylation is redundant as it leads back to starting material 9.210, whereas C-alkylation leads to the product 9.212. ... 

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. 

Transfer of chirality in aldol reactions has been attempted using / -allenyl ester enolates. These ambident nucleophiles have an axis of chirality, and such compounds have been less utilized in stereoselective reactions. They are prepared by transmetallation of the... 

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 . 

An interesting class of chiral enolates are allenyl enolates. These ambident nucleophiles bear an axis of chirality. Krause and coworkers have found that an axis to center chirality transfer takes place in the aldol reaction of chiral magnesium allenyl enolate with pivalic aldehyde . The aldol reaction proceeds with good diastereofacial selectivity if... 

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

The sulfur analogues of enolates have recently received attention in the context of synthetic applications. Thiocarbonyl compounds bear a-protons which are rather acidic. Kresge et al. [120] has shown that their pKas are 10 units less than those of carbonyl compounds. Thus enethiolates are easily formed with a variety of bases, and they exhibit thermal stability [1]. They are ambident nucleophiles and the sulfur vs carbon regiochemistry has been rationalised by Anh [119] using frontier orbital treatment. 

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. 

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. ... 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

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

Enolates and aza enolates are so-called ambident nucleophiles. This term describes nucleophiles with two nucleophilic centers that are in conjugation with each other. In principle, enolates and aza enolates can react with electrophiles either at the heteroatom or at the car-banionic C atom. Ambidoselectivity occurs if one of these alternative modes of reaction dominates. 

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. 

Enolates are nucleophiles, and as such they react with many electrophiles. Because an eno-late is resonance stabilized, however, it has two reactive sites— the carbon and oxygen atoms that bear the negative charge. A nucleophile with two reactive sites is called an ambident nucleophile. In theory, each of these atoms could react with an electrophile to form two different products, one with a new bond to carbon, and one with a new bond to oxygen. 

Ambident nucleophiles are considered to be bidentate molecules whose nucleophilic centres have direct chemical interaction with each other, such as a ketone with its enol-carbanion tautomers. 

With the practical methods for the generation of F-enolates in hand, we next turned attention to the chemistry of F-enolates. The fundamental questions to be answered are as follows, (a) Do F-enolates show the ambident nucleophilic reactivity like hydrocarbon enolates (b) How about the aldol reactivity 7 (c) Do F-enolates exhibit any unique reactivities In other words, do F-enolates show rather the electrophilic reactivity of perfluoroolefins With these questions in mind, we carried out reactions of F-enolates with a wide variety of reagents. 

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... 

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... 

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]. 

Enolates are called ambident nucleophiles (ambi is Latin for both and dentis Latin for teeth ), because they possess two nucleophilic sites, each of which can attack an electrophile. When the oxygen atom attacks an electrophile, it is called O-attack and when the a carbon attacks an electrophile, it is called C-attack. 

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