Enolate anion as nucleophile

Alkylation of the a-position of suitable carboxylic acid derivatives may be achieved using the enolate anion as nucleophile in a typical Sn2 reaction (compare Section 10.2). In the example shown, the... 

Stabilized enolate anions as nucleophiles formation of carbon-carbon bonds (P condensation)... 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

Acetyl-CoA is a good biochemical reagent for two main reasons. First, the a-protons are more acidic than those in ethyl acetate, comparable in fact to a ketone, and this increases the likelihood of generating an enolate anion. As explained above, this derives from sulfur being larger than oxygen, so that electron donation from the lone pair that would stabilize the neutral ester is considerably reduced. This means it is easier for acetyl-CoA to lose a proton and become a nucleophile. Second, acetyl-CoA is actually a better electrophile than ethyl acetate. 

These are reacted together in basic solution. It can be deduced that the 1,3-diketone is more acidic than the monoketone substrate, so will be ionized by removal of a proton from the carbon between the two carbonyls to give the enolate anion as a nucleophile. This attacks the a,P-unsaturated ketone in a Michael reaction. It is understandable that this large nucleophile prefers to attack the unhindered -position rather than the more congested ketone carbonyl. 

In this case, we formulate the Claisen reaction between two ester molecules as enolate anion formation, nucleophilic attack, then loss of the leaving group. Now reverse it. Use hydroxide as the nucleophile to attack the ketone carbonyl, then expel the enolate anion as the leaving group. All that remains is protonation of the enolate anion, and base hydrolysis of its ester function. 

Examples of such molecules include conjugated nucleophiles such as the enolate anion. Such nucleophiles have potentially two attacking atoms (in the case of the enolate anion, the oxygen or the a-carbon) reaction conditions affect which will be the more prevalent species. Other examples include the cyanide (CN ) and the nitrite (NO2 ) ions. 

One possibility we have not yet considered is combining d) with the other three that is using the enolate anion as the nucleophile in these reactions. 

It is known that acetone enolate anion does not react with primary alkyl radicals, and that nitromethane anion is not capable of initiating the SRN1 reactions even under irradiation [99]. Thus, the photo stimulated reactions of 25 with nitromethane anion as nucleophile and acetone enolate anion as entrainment reagent (which enables SRN1 initiation but cannot compete with the coupling of the methylene radical with nitromethane anion after cyclization) render the cyclized products 26 (Sch. 25) [98]. 

More recent examples of nucleophilic aromatic substitution reactions include the reactions of C6F6 with the superoxide ion, 02 to give F and, presumably, C6F502 278 and with the acetic acid enolate anion, as shown in Scheme 42, which also indicates how the anionic reagent was formed279. It should be noted that reaction of gas-phase F" with a suitably silylated precursor is one of the best and most specific reactions to prepare gas-phase anions280. 

Typical carbonyl compounds behave as weak C-H acids. If, for example, one generates the enolate anion of acetone using even a relatively strong conventional base, such as sodium ethoxide, the resultant equilibrium will be shifted far to the left (Scheme 2.21). Carbonyl compounds themselves, as we soon will see, are active electrophiles due to the presence of the partially positive carbonyl carbon. Hence, the nucleophilic enolate generated in the above system can react with non-ionized acetone molecules abundantly present in this equilibrium. This reaction is the well-known aldol condensation (Scheme 2.21). Although useful in its own right, its ease of occurrence creates serious obstacles for the use of an in situ generated enolate anion as a nucleophile in reactions with other electrophiles. 

Similar information is available for other bases. Lithium phenoxide (LiOPh) is a tetramer in THF. Lithium 3,5-dimethylphenoxide is a tetramer in ether, but addition of HMPA leads to dissociation to a monomer. Enolate anions are nucleophiles in reactions with alkyl halides (reaction 10-68), with aldehydes and ketones (reactions 16-34, 16-36) and with acid derivatives (reaction 16-85). Enolate anions are also bases, reacting with water, alcohols and other protic solvents, and even the carbonyl precursor to the enolate anion. Enolate anions exist as aggregates, and the effect of solvent on aggregation and reactivity of lithium enolate anions has been studied. The influence of alkyl substitution on the energetics of enolate anions has been studied. ... 

There are two major reactions of enolates (1) displacement reactions with alkyl halides or other suitable electrophiles and (2) nucleophilic addition to carbonyl compounds. Reaction of 58 with butanal to give 59 and reaction of 61 with bromopentane to give 62 are simple examples of each process. Enolate anions function as carbon nucleophiles and their reactions are fundamentally the same as those discussed in Section 8.3.C for acetylides. Although there are interesting differences, treating an enolate anion as a carbon nucleophile is very reasonable. 

This anion will not be produced from a B-ketoester that has no hydrogens on the carbon between the two carbonyl groups. Such B-ketoesters would result from the Claisen condensation of an ester having only one a hydrogen. Since our problem uses ethyl acetate, the B ketoester anion is formed. This anion, like the enolate anion, is nucleophilic enough to attack the partially positively charged carbonyl carbon of an ester. Here, 0-acylation is much less thermodynamically stable than is C-acylation. Hence, the reaction of the B-ketoester anion with the ester (using ethyl acetoacetate and ethyl acetate as in our problem) is ... 

It is clear from this last example that an enolate anion behaves as a carbon nucleophile and gives the same sort of acyl addition reaction as another previously discussed carbanion, an alkyne anion (see Chapter 18, Section 18.3.2). The products are different, of course, but from the standpoint of comparing reactions, the only real difference between an enolate anion and an alkyne anion is the structure and complexity of the enolate anion as a carbon nucleophile and the functionality in the fined acyl addition product. 

The acyl addition and acyl substitution reactions of enolate anions presented in this chapter clearly show that enolate anions are nucleophiles. In Chapter 11 (Section 11.3), various nucleophiles reacted with primary and secondary alkyl halides via Sn2 reactions. Enolate anions also react with alkyl halides via 8 2 reactions in what is known as enolate alkylation. 

A typical reaction that uses an amino acid derivative involves initial conversion to an enolate anion. This nucleophilic species is then reacted with an alkyl halide or a carbonyl derivative. An example that produces a new amino acid is the reaction of the ethyl ester of n-benzyl glycine with lithium diisopropylamide to give the enolate. Subsequent reaction with the mixed anhydride shown below proceeded with displacement of acetate to give /.22J.13 Acid hydrolysis generated a P-keto amino acid, which decarboxylated under the reaction conditions to give 4-oxo-5-aminopen-tanoic acid 1.156, also known as 5-aminolevulinic acid). 

In some respects, the alkylation of enolate anions resembles nucleophilic substitution. We recall that many nucleophiles displace leaving groups from primary alkyl halides by an Sj 2 mechanism (Section 9.3). A similar reaction occurs with secondary alkyl halides, but competing elimination reactions also occur. Primary alkyl halides react with carbanions, such as the alkynide ion, by an Sj 2 mechanism. (Secondary alkyl halides react not only in displacement reactions but also in elimination reactions because the alkynide ion is a strong base.)... 

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... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

Vinyl sulfones, being good Michael acceptors, have been regarded as useful reagents for carbon-carbon bond formation. Nucleophiles used often are organometallic reagents, enamines and enolate anions and the Michael addition products are usually obtained in... 

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