Carbanions relative acidity

A hydrogen attached to the a carbon atom of a p keto ester is relatively acidic Typical p keto esters have pA values of about 11 Because the a carbon atom is flanked by two electron withdrawing carbonyl groups a carbanion formed at this site is highly stabi hzed The electron delocalization m the anion of a p keto ester is represented by the res onance structures... 

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... 

It has been found that there is often a correlation between the rate of deprotonation (kinetic acidity) and the thermodynamic stability of the carbanion (thermodynamic acidity). Because of this relationship, kinetic measurements can be used to construct orders of hydrocarbon acidities. These kinetic measurements have the advantage of not requiring the presence of a measurable concentration of the carbanion at any time instead, the relative ease of carbanion formation is judged from the rate at which exchange occurs. This method is therefore applicable to very weak acids, for which no suitable base will generate a measurable carbanion concentration. 

The kinetic method of determining relative acidity suffers from one serious complication, however. This complication has to do with the fate of the ion pair that is formed immediately on removal of the proton. If the ion pair separates and difiuses into the solution rapidly, so that each deprotonation results in exchange, the exchange rate is an accurate measure of the rate of deprotonation. Under many conditions of solvent and base, however, an ion pair may return to reactants at a rate exceeding protonation of the carbanion by the solvent. This phenomenon is called internal return ... 

Base catalyzed condensation reactions of esters and ketones have an additional factor of importance in determining the product, and this is the fact that the overall reaction, as well as the intermediate steps, is highly reversible. The final product may be rate or equilibrium determined, and in the latter case the result may depend on the relative acidity of the various possible products. In a highly basic medium the product will be partly in the form of a salt and the stability of the salt is then a product-determining factor. Failure of a condensation to take place may be due either to an insufficiently high concentration of carbanions or to the instability of the product. The reactions of ethyl isobutyrate will illustrate both points.419... 

In this section we shall examine in detail the role of n—a interactions in carbanion chemistry. Carbanion stability as well as relative acidities of organic molecules are important probes of n—a interactions. 

The proton in the thiazolium ring is relatively acidic (p Ta about 18) and can be removed by even weak bases to generate the carbanion or ylid an ylid is a species with positive and negative charges on adjacent atoms. This ylid is an ammonium ylid with extra stabilization provided by the sulfur atom. 

Relatively acidic carbon acids such as malonic esters and jS-keto esters were the first class of carbanions for which reliable conditions for alkylation were developed. The reason being that these carbanions are formed using easily accessible alkoxide ions. The preparation of 2-substiuted /i-kcto esters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.5 are useful for the synthesis of ketones and carboxylic acids, since both /1-ketoacids and malonic acids undergo facile decarboxylation ... 

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

In addition to stable cations, triarylmethyl compounds form stable carbanions. Because of this the corresponding hydrocarbons are relatively acidic compared to simple alkanes. They react readily with strong bases such as sodium amide, and the resulting carbanions, like the cations, are intensely colored ... 

In concerted E2 eliminations from monofluorides the orientation of elimination is controlled by the relative acidities of 3-hydrogen in a process that is consistent with a poor leaving group and a transition state with high carbanionic character of the (S-carbon atom [13] (Figure 6.8). 

Information about the acidities or relative acidities of the haloforms has been obtained from kinetic studies under conditions where low concentrations of the carbanion are present and decomposition is unimportant. Extensive studies of this type have been carried out by Hine et al. [164]. Exchange of deuterium from CDX3 in aqueous buffer solutions (98)... 

The additional stereochemical control available in carbanions relative to alkoxides arises both from the extra ligation about carbon and the contributions of the metal. The stereochemistry of hydride transfer from organostannanes has been particularly well investigated. Coordinatively saturated metals like tin function less well as Lewis acids in a cyclic mechanism, and tend to induce hydride loss through an anti-... 

It may rather be that in the case of third row substituents like R4P the relative acidity of cyclopropyl and isopropyl hydrogens is not as indicative of the carbanion configuration as in the case with the second row substituents C(0)R, CN and possibly NO2. As far as cyclopropyl sulfones are concerned one would therefore predict that the corresponding a-sulfonyl cyclopropyl anions may have a pyramidal configuration. The deprotonation of cyclopropyl phosphonates, followed by reaction with aldehydes, was recently published by Hirao and coworkers ... 

The most utilized Umpolung strategy is based on formyl and acyl anion equivalents derived from 2-lithio-l,3-dithiane species. These are readily generated from 1,3-dithianes (thioacetals) because the hydrogens at C(2) are relatively acidic (p f 31). In this connection it should be noted that thiols (EtSH, pi 11) are stronger acids compared to alcohols (EtOH, 16). Also, the lower ionization potential and the greater polarizability of the valence electrons of sulfur compared to oxygen make the divalent sulfur compounds more nucleophilic in Sj,2 reactions. The polarizability factor may also be responsible for the stabilization of carbanions a to sulfur. ... 

Both tetrahydroisoquinoline amides and formamidines may be successively alkylated at the l-posi-tion. The second deprotonation is somewhat less facile, however, since it entails removal of a methine proton. In applying this methodology to the synthesis of naturally occurring tetrahydroisoquinoline alkaloids, a problem is encountered. The presence of oxygen substituents on the aromatic ring destabilizes the benzylic carbanion, and since this effect is felt in the transition state, the acidity of the benzylic protons is lowered. Thus, successive alkylation of t-butylformamidines of oxygenated tetrahydroisoquinolines is not possible. To circumvent the decreased acidity, a study of the relative acidity of various N-substituted formamidines was done- that resulted in a solution to the problem. As shown in Scheme 15, successive alkylation of the methoxymethylphenylformamidine (9) is readily achieved. 

Carbonyl compounds C=0 have two major resonance structures, R.2C=0 <—> R2C-6. In the second resonance structure, C is electron-deficient, so carbonyl compounds are good electrophiles. Carbonyl groups with a-hydrogen atoms are relatively acidic compounds, because the carbanions produced upon removal of the H are stabilized by resonance with the carbonyl group 0=CR-CR2 <—> 0-CR=CR2. The enolate anions that are thereby obtained are nucleophilic at the a-carbon and on O. Under basic conditions, then, carbonyl compounds are electrophilic at the carbonyl carbon and nucleophilic at the a-carbons (if they have H atoms attached). All the chemistry of carbonyl compounds is dominated by this dichotomy. 

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