Generation of Carbanions by Deprotonation

By comparing the approximate pA values of the conjugate acids of the bases with those of the carbon acid of interest, it is possible to estimate the position of the acid-base equilibrium for a given reactant-base combination. If we consider the case of a simple alkyl ketone in a protic solvent, for example, it can be seen that hydroxide ion and primary alkoxide ions will convert only a small fraction of such a ketone to its anion. 

The slightly more basic tertiary alkoxides are comparable to the enolates in basicity, and a somewhat more favorable equilibrium will be established with such bases  

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( NH2), the conjugate base of DMSO (sometimes referred to as the dimsyl anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of w-butyllithium to diisopropylamine, is widely used as a strong 

Carbon acid P DMSO Common bases P DMSO 

Sodium hydride and potassium hydride can also be used to prepare enolates from ketones. The reactivity of the metal hydrides is somewhat dependent on the means of preparation and purification of the hydride.5 

The efficient generation of a significant equilibrium concentration of a carbanion requires choice of a proper Brpnsted base. The equilibrium will only favor carbanion formation when the acidity of the carbon acid is greater than that of the conjugate acid of the base used for deprotonation. Acidity is quantitatively expressed as pX,  

Carbon acid pK- P DMSO Common bases pK P DMSO 

From the pX values collected in Table 1.1, an ordering of some substituents with respect to their ability to stabilize carbanions can be established. The order suggested is NO2 COR CN CO2R SO2R SOR Ph SR H R. 

---

The specific generation of carbanions in the gas phase by proton abstraction is associated with several problems. In the first place, even simple organic hydrocarbons may have more than one acidic site, and deprotonation may therefore give rise to a mixture of isomers. For example, proton abstraction by OH - or NH2 from propyne 310 generates both the propargyl (311) and the methylacetylide anion 312150 (reaction 121). 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

In the discussion of the relative acidity of carboxylic acids in Chapter 1, the thermodynamic acidity, expressed as the acid dissociation constant, was taken as the measure of acidity. It is straightforward to determine dissociation constants of such adds in aqueous solution by measurement of the titration curve with a pH-sensitive electrode (pH meter). Determination of the acidity of carbon acids is more difficult. Because most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. Any strong base will deprotonate the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, tetrahydrofuran (THF), and dimethoxyethane (DME) are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as DMSO and cyclohexylamine are used in the preparation of strongly basic carbanions. The high polarity and cation-solvating ability of DMSO facilitate dissociation... 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

The assumed mechanism includes the activation of acetonitrile by iV-coordination to the metal center, followed by deprotonation with DBU. The generated carbanion, iV-coordinated to the ruthenium atom, adds to the corresponding electrophile, while the presence of the sodium salt allows the regeneration of the ruthenium catalyst. Both various types of aldehydes as well as activated aromatic imines have been successfully employed as electrophiles, providing the corresponding adducts 171 in good to high yields. 

The finding that thiamine, and even simple thiazolium ring derivatives, can perform many reactions in the absence of the host apoenzyme has allowed detailed analyses of its chemistry [33, 34]. In 1958 Breslow first proposed a mechanism for thiamine catalysis to this day, this mechanism remains as the generally accepted model [35]. NMR deuterium exchange experiments were enlisted to show that the thiazolium C2-proton of thiamine was exchangeable, suggesting that a carbanion zwitterion could be formed at that center. This nucleophilic carbanion was proposed to interact with sites in the substrates. The thiazolium thus acts as an electron sink to stabilize a carbonyl carbanion generated by deprotonation of an aldehydic carbon or decarboxylation of an a-keto acid. The nucleophilic carbonyl equivalent could then react with other electro-... 

The aim in the previous sections was to generate chiral carbanions with enantiomeric excess by the interaction of (—)-sparteine (11) during the deprotonation. The addition of... 

The formation of carbanions, according to Scheme 6, has been much studied but has proved to be of little preparative use. The benzyl anion, generated from benzyl-dimethylsulphonium tosylate, reacted with acrylonitrile but the addition product was formed in only low yield Similarly the reactive ylid formed by deprotonation of trimethylsulphonium salts has been cathodically generated and trapped by several aldehydes and ketones as well as ethyl maleate and fumarate examples are given in Scheme 7. For the best case (benzophenone), the epoxide was formed in 40%... 

Carbanions at C(2) of the aziridine ring may be generated by deprotonation or by exchange, e.g. tin-lithium. A major problem with the deprotonation approach is the necessity of a strong base which may also react by a nucleophilic ring-opening process. /V-(f-Butoxycarbonyl)aziridines may be deproto-nated with BusLi/TMEDA, as shown in Scheme 20 (94JOC276). 

Based on these reactivities various derivatives of carbenes, such as the aminocarbene 238, are prepared by displacement of the OR group in 237 with amine via addition elimination, analogous to transesterification [74,75], As an example the carbanion 240, generated by deprotonation of 239, attacks ethylene oxide to give the lactone equivalent 241, which is further alkylated by chloromethyl methyl ether, again at the -position. Finally the oc-methylene-y-lactone 242 is obtained by oxidative demetallation with a Ce(TV) salt [76],... 

The more acidic a C,FI group, the less basic and nucleophilic will the corresponding carbanion usually be. Consequently, carbanions generated by deprotonation of strongly acidic C,FI groups will react slowly with electrophiles, and are usually difficult to alkylate, as illustrated by the examples in Scheme 5.3. Monodeprotonated... 

Another group of unstable carbanions are those with antiaromatic character (Scheme 5.71). Thus, cyclopropenyl anions or oxycyclobutadienes, generated by deprotonation of cyclopropenes or cyclobutenones, respectively, will be highly reactive and will tend to undergo unexpected side reactions. Similarly, cyclopentenediones are difficult to deprotonate and alkylate, because the intermediate enolates are electronically related to cyclopentadienone and thus to the antiaromatic cyclopenta-dienyl cation. 

---