Carboxyl carbon resonance stabilization

Carbonyl compounds are more acidic than alkanes for the same reason that carboxylic acids are more acidic than alcohols (Section 20.2). In both cases, the anions are stabilized by resonance. Enolate ions differ from carboxylate ions, however, in that their two resonance forms are not equivalent—the form with the negative charge on oxygen is lower in energy than the form with the charge on carbon. Nevertheless, the principle behind resonance stabilization is the same in both cases. 

In the first step of the conversion catalyzed by pyruvate decarboxylase, a carbon atom from thiamine pyrophosphate adds to the carbonyl carbon of pyruvate. Decarboxylation produces the key reactive intermediate, hydroxyethyl thiamine pyrophosphate (HETPP). As shown in figure 13.5, the ionized ylid form of HETPP is resonance-stabilized by the existence of a form without charge separation. The next enzyme, dihydrolipoyltransacetylase, catalyzes the transfer of the two-carbon moiety to lipoic acid. A nucleophilic attack by HETPP on the sulfur atom attached to carbon 8 of oxidized lipoic acid displaces the electrons of the disulfide bond to the sulfur atom attached to carbon 6. The sulfur then picks up a proton from the environment as shown in figure 13.5. This simple displacement reaction is also an oxidation-reduction reaction, in which the attacking carbon atom is oxidized from the aldehyde level in HETPP to the carboxyl level in the lipoic acid derivative. The oxidized (disulfide) form of lipoic acid is converted to the reduced (mer-capto) form. The fact that the two-carbon moiety has become an acyl group is shown more clearly after dissocia-... 

SN Reactions at the Carboxyl Carbon The Influence of Resonance Stabilization of the Reacting C=0 Double Bond on the Reactivity of the Acylating Agent... 

Carboxylic acids can be activated in situ as mixed anhydrides B (Figure 6.14) that are mixed anhydrides of a carboxylic acid and a carbonic acid half ester. As can be seen from Table 6.1, in anhydrides of this type the C=0 double bond of the carboxylic acid moiety is stabilized less by resonance than the C=0 double bond of the carbonic acid moiety. Therefore, a nucleophile chemoselectively reacts with the carboxyl carbon of the carboxylic and not the carbonic acid ester moiety. 

The last but one in situ procedure for activating carboxylic acids is shown in Figure 6.16. There, the oc-chlorinated A-methylpyridinium iodide A reacts with the carboxylic acid by an SN reaction at a pyridine carbon. This leads to the pyridinium salt C, presumably via the Meisenheimer complex B and its deprotonation product D as intermediates. The activated carboxylic acid C is not only an aryl ester but one in which the aryl group is positively charged. This charge keeps the single-bonded O atom of this species completely from providing any resonance stabilization by its +M effect to the C=0 double bond (cf. discussion of Table 6.1). 

While most of the chemistry discussed in this chapter has been developed in the past decade, several important methods have withstood the test of time and have made important contributions in areas such as natural product synthesis. Methods such as cuprate acylation and the addition of organolithiums to carboxylic acids have continued to enjoy widespread use in organic synthesis, whereas older methods including the reaction of organocadmium reagents with acid halides, once virtually the only method available for acylation, has not seen extensive utilization recently. In the following discussion, we shall be interested in cases where selective monoacylation of nonstabilized carbanion equivalents has been achieved. Especially of concern here are carbanion equivalents or more properly organometallics which possess no source of resonance stabilization other than the covalent carbon-metal bond. Other sources of carbanions that are intrinsically stabilized, such as enolates, will be covered in Chapter 3.6, Volume 2. 

To satisfy the yields of aromatic aldehydes obtained (Table I), rates ki and must be considerably greater than the heterolysis rate, 3. This seems reasonable because equilibration of V and VII when aldehyde is removed should occur readily in the aromatic series where Ri can offer substantial resonance stabilization to the transition state, VI, by enhancing the cationic character of the carbonyl carbon. In Briner s early work (1,2) on the hydrolysis of stilbene and isoeugenol ozonides, advantage was not taken of these equilibria and rate differences. As a consequence almost half of the final cleavage products after extensive hydrolytic treatment without aldehyde removal were carboxylic acids, IX. 

We don t usually look to aromatic systems for examples of inductive effects, because the pi system of electrons is ripe for resonance effects. However, in analyzing the resonance forms of phenoxide on the next page, it becomes apparent that the negative charge is never distributed on the meta carbons. Meta substituents cannot exert any resonance stabilization or destabilization at the meta position, substituents can exert only an inductive effect. The series of phenols demonstrates this phenomenon, consistent with aliphatic carboxylic acids. 

The experimental conditions for the carboxylation of allenyllithium are governed by the consideration that introduction of the COOLi group renders the allenic protons more acidic (resonance stabilization). If the normal order addition is used (introduction of C02 into the solution of allenyllithium), the allenic carboxylate primarily formed may easily be deprotonated by the strongly basic allenyllithium. The new species (either LiCH=C=CHCOOLi or H2C=C=C(Li)COOLi) may react also with C02. To avoid this situation the solution of allenyllithium is gradually added to a strongly cooled solution of carbon dioxide in THF. As usual, liberation of the acid occurs by adding mineral acid. In view of the possibility of an acid-catalyzed cyclization to a lactone too strongly acidic conditions should be avoided ... 

Sodium Carbonate can also be used as the base in the tosylation of amines, as shown in the reaction of anthranilic acid with tosyl chloride. There was no cotipeting nucleophilic attack at sulfur by the resonance-stabilized carboxylate group (eq 32). ... 

Acetoacetic ester synthesis (Section 18.6) A sequence of reactions involving removal of the a-hydrogen of ethyl 3-oxobutanoate (ethyl acetoacetate, also called acetoacetic ester ), creating a resonance-stabilized anion which then can serve as a nucleophile in an Sn2 reaction. The a-carbon can be substituted twice the ester functionality can be converted into a carboxylic acid which, after decarboxylation, yields a substituted ketone. 

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