Nucleophilic Substitution with Enolate Anions

The synthetic chemistry of enolate anions is centered on their nucleophilic and basic properties. Accordingly these ions participate in SN2 reactions with suitable alkyl compounds  

17 Carbonyl Compounds II. Enols Enolate Anions. Unsaturated and Polycarbonyl Compounds 

However, there are a number of complicating factors to consider. First, the basic conditions needed to form the enolate ions often lead to side reactions such as aldol addition and E2 elimination of RX compounds. Aldol addition is minimized if the carbonyl compound is a ketone with a structure unfavorable for aldol addition or if all of the carbonyl compound is converted to its enolate. To convert all of a simple carbonyl compound to its enolate usually requires a very strong base, such as NH2 in an aprotic solvent or liquid ammonia. Because the enolate anion itself is a strong base, best results are obtained when the halide, RX, does not undergo E2 reactions readily. 

The second complication arises if the alkyl compound reacts with both carbon and oxygen of the nucleophilic enolate anion. The carbon product is the result of C-alkylation, whereas the oxygen product is the result of O-alkylation  

The possibility of the enolate anion acting as if its charge were effectively concentrated on carbon or on oxygen was discussed previously in connection with aldol addition (Section 17-3B). However, the situation there was quite different from the one here, because aldol addition is easily reversible, whereas alkylation is not. Furthermore, while the aldol reaction involving C-O bond formation is unfavorable (AH° = + 20 kcal mole-1) compared to C-C bond formation (AHn = —4 kcal mole-1), both O- and C-alkylation of the anion have AH° 0 (see Exercise 17-64). 

---

S l reactions of the above substrates in liquid ammonia also occur with a fair variety of other nucleophiles Ph2As"31, PhSe- and PhTe 32and PhS-33. With carbanionic nucleophiles, however, only reductive dehalogenation products are found. Substitution with enolate anions is successful in DMSO as solvent34. 

Nucleophilic photosubstitution with enolate anions continues to attract attention. p-Dihalobenzenes react to give doubly substituted products (91), although... 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

A particularly interesting combination of allyl ligand structure and the high reactivity toward aryl halides leads to the synthesis equivalent of nucleophilic aromatic substitution by enolate anions, but under completely different conditions (Scheme 51). In this example, the 2-methoxyallyl ligand is equivalent to an acetone enolate anion, but reacts with very different functional group compatibility (no polar... 

This process is much less common than nucleophilic substitution by alkynide anions and the actual mechanisms of the reactions in which electrophilic substitution of an sp-carbon appears to occur probably do not involve simple substitution. Kende and coworkers, for example, have reacted tertiary enol-ate anions with chloroalkynes and obtained the corresponding alkylated products (Scheme 32). These... 

Alkynyl(phenyl)iodonium salts have found synthetic application for the preparation of various substituted alkynes by the reaction with appropriate nucleophiles, such as enolate anions [980,981], selenide and telluride anions [982-984], dialkylphosphonate anions [985], benzotriazolate anion [986], imidazolate anion [987], N-functionalized amide anions [988-990] and transition metal complexes [991-993]. Scheme 3.291 shows several representative reactions the preparation of Ai-alkynyl carbamates 733 by alkynylation of carbamates 732 using alkynyliodonium triflates 731 [989], synthesis of ynamides 735 by the alkyny-lation/desilylation of tosylanilides 734 using trimethylsilylethynyl(phenyl)iodonium triflate [990] and the preparation of Ir(III) a-acetylide complex 737 by the alkynylation of Vaska s complex 736 [991]. 

The reaction of carbon nucleophiles with ketones or aldehydes proceeds by acyl addition, as described in Chapter 18. The reaction of carbon nucleophiles with acid derivatives proceeds by acyl substitution, as described in Chapter 20. Carbon nucleophiles included cyanide, alkyne anions, Grignard reagents, organolithium reagents, and organocuprates. Alkyne anions are formed by an acid-base reaction with terminal alkynes (RC=C-H RCsCr). In this latter transformation, it is clear that formation of the alkyne anion relies on the fact that a terminal alkyne is a weak carbon acid. Other carbon acids specifically involve the proton on an a-carbon in aldehydes, ketones, or esters. With a siiitable base, these carbonyl compounds generate a new type of carbon nucleophile called an enolate anion. 

Claisen Condensation (Section 19.3A) The product of a Claisen condensation is a j8-ketoester. Condensation occurs by nucleophilic acyl substitution in which the attacking nucleophile is the enolate anion of an ester. The Claisen condensation mechanism involves reaction of one ester molecule with base to form an enolate anion, which reacts as a nucleophile with another molecule of ester to give a tetrahedral carbonyl addition intermediate, in which the RO" group is lost to give a /3-ketoester, which is deprotonated at the a position by the RO". 

The chlorine at C-8 in (27 R = H) and in (27 R = Cl) has been replaced with a variety of N-, 0-, and S-containing nucleophiles the use of p-thiocresol gives substitution of both chlorine substituents. A closely related compound, 2-chloro-3-ethoxycarbonyl-cyclohepta[f>]pyrrole, with enolate anions gives a variety of substitution and addition products, dependent upon the reaction conditions. ... 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of cf-bromo carbonyl compounds (a -synthons) with enolate type anions (d -synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

The SET mechanism is chiefly found where X = I or NO2 (see 10-104). A closely related mechanism, the SrnE takes place with aromatic substrates (Chapter 13). In that mechanism the initial attack is by an electron donor, rather than a nucleophile. The Srn 1 mechanism has also been invoked for reactions of enolate anions with 2-iodobicyclo[4.1.0]heptane. An example is the reaction of l-iodobicyclo[2.2.1]-heptane (15) with NaSnMe3 or LiPPh2, and some other nucleophiles, to give the substitution product. Another is the reaction of bromo 4-bromoacetophenone (16) with Bu4NBr in cumene. " The two mechanisms, Sn2 versus SET have been compared and contrasted. There are also reactions where it is reported that radical, carbanion, and carbene pathways occur simultaneously. ... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Substitution of a carbon monoxide ligand of complexes, such as 1, by the more electron-donating triphenylphosphane group (see Section 1.1.1.3.4.1.3.) provides chiral monophos-phane complexes, such as 3. Monophosphane complexes in general lack sufficient electrophilic-ity to react with amines or thiols, but react readily with amine anions at the /J-position, producing enolate anions such as 4, which may be quenched stereoselectively at the a-carbon by electrophiles46 (see Section 1.1.1.3.4.1.3.). The conformational and stereochemical issues involved are essentially identical to those already discussed in this section for the 1,4-additions of carbon nucleophiles. 

Photostimulated, S r k 1 reactions of carbanion nucleophiles in DMSO have been used to advantage in C—C bond formation (Scheme 1).25-27 Thus, good yields of substitution products have been obtained from neopentyl iodide on reaction with enolates of acetophenone and anthrone, but not with the conjugate base of acetone or nitromethane (unless used in conjunction, whereby the former acts as an entrainment agent).25 1,3-Diiodoadamantane forms an intermediate 1-iodo mono substitution product on reaction with potassium enolates of acetophenone and pinacolone and with the anion of nitromethane subsequent fragmentation of the intermediate gives derivatives of 7-methylidenebicyclo[3.3.1]nonene. Reactions of 1,3-dibromo- and 1-bromo-3-chloro-adamantane are less effective.26... 

The normal U-shaped Hammett plots were found for both the catalysed [by a copper(II)salen complex (31)] and uncatalysed asymmetric alkylation of enolates by substituted benzyl bromides,126 indicating that both reactions occur via an. S N2 mechanism (Scheme 15). Because both reactions were faster when electron-withdrawing substituents were on the benzyl bromide, it was concluded that there was more bond formation than bond rupture in the. S N2 transition states. Because the curvature of the Hammett plot was greater for the catalysed reaction, it was concluded that the catalysed reaction has a later transition state with a greater negative charge on Ca. The role of the catalyst was to increase the nucleophilic character of the enolate anion. 

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. 

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. 

On the other hand, Russell and coworkers have proposed that the substitution and enolate dimerization products, formed in the reactions of 2-substituted-2-nitropropanes (XCMe2N02, X = Cl, N02, / -MePhS02) with nucleophiles that easily lose one electron, such as the mono enolate anions ArC(OLi)=CHR (R = Me, Et, z -Pr, zz-Bu) and t-BuC(OLi)=CH2, can be rationalized on the basis of a free radical chain mechanism involving bimolecular substitution or ET reactions between the enolate anion and the intermediate nitroalkane radical anion62. An S 2 -type mechanism has also been recently suggested for the reaction of pentafluoronitrobenzene with several nucleophiles in aqueous media65. 

Russell and coworkers62,109,110 have shown that simple enolates undergo free radical-chain nucleophilic substitution reactions with a-chloronitroalkanes by an SRN2 rather than an S l mechanism, and competition with a chain dimerization process was also observed. Using two equivalents of the enolate anion in the reaction allows complete elimination of HN02 to yield a,/i-unsaturated ketones. The synthetic potential of these reactions has also been reported110. 

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations ... 

These reactions consist of two steps. The first is the formation of a stabilized anion—usually (but not always) an enolate—by deprotonation with base. The second is a substitution reaction attack of the nucleophilic anion on an electrophilic alkyl halide. All the factors controlling SnI and Sn2 reactions, which we discussed at length in Chapter 17, are applicable here, step l formation of enolate anion step 2 alkylation (SN2 reaction with alkyl halide)... 

A more generally useful reaction is the self-condensation of simple substituted acetates RCH2C02Et. These work well under the same conditions (EtO- in EtOH), The enolate anion is formed first in low concentration and in equilibrium with the ester. It then carries out a nucleophilic attack on the more abundant unenolized ester molecules. 

In earlier chapters we revealed how some reactive intermediates can be prepared, usually under special conditions rather different from those of the reaction under study, as a reassurance that some of these unlikely looking species can have real existence. Intermediates of this kind include the carboca-tion in the S l reaction (Chapter 17), the cations and anions in electrophilic (Chapter 22) and nucleophilic (Chapter 23) aromatic substitutions, and the enols and enolates in various reactions of carbonyl compounds (Chapters 21 and 26-29). We have also used labelling in this chapter to show that symmetrical intermediates are probably involved in, for example, nucleophilic aromatic substitution with a benzyne intermediate (Chapter 23). 

---