Resonance in carboxylates

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group. Resonance in carboxylate anions is more effective than resonance in carboxylic acids, acyl chlorides, anhydrides, thioesters, esters, and amides. 

For many years, resonance in carboxylate ions was emphasized when explaining the acidity of carboxylic acids. Recently, however, it has been suggested that the inductive effect of the carbonyl group may be more important. It seems clear that, even though their relative contributions may be a matter of debate, both play major roles. 

Physical data support the importance of resonance in carboxylate ions. In formic acid molecules, the two carbon-oxygen bonds have different lengths. But in sodium formate, both carbon-oxygen bonds of the formate ion are identical, and their length is between those of normal double and single carbon-oxygen bonds. 

Infrared spectroscopy can also be used to probe resonance in carboxylic acid derivatives. The dipolar resonance structure weakens the C=0 bond and causes a corresponding decrease in the carbonyl stretching frequency (Table 20-2). The IR data for carboxylic acids reported in Section 19-3 refer to the common dimeric form, in which hydrogen bonding reduces the stretching frequencies of both the 0-H and C=0 bonds to about 3000 and 1700 cm respectively. A special technique—vapor deposition at very low temperature—allows the IR spectra of carboxylic acid monomers to be measured, for direct comparison with the spectra of carboxylic acid derivatives. Monomeric acetic acid displays vc=o at 1780 cm similar to the value for carboxylic anhydrides, higher than that for esters, and lower than that of halides, consistent with the degree of resonance delocalization in carboxylic acids. 

The extent of resonance in carboxylic acid derivatives is also seen in their basicity (protonation at the carbonyl oxygen) and acidity (enolate formation). In all cases, protonation requires strong acid, but it gets easier as the electron-donating ability of the L group increases. Protonation is important in acid-catalyzed nucleophilic addition-elimination reactions. 

Resonance description of electron delocalization in carboxylate anion... 

On the other hand, methyl substituents have a weak electron-donating effect opposing that of the aromatic ring. This also favours resonance in the non-ionized acid. There is only a modest effect on acidity, except when the methyl is in the ortho position, where the effect is closer to the carboxyl group. However, ortho substituents add a further dimension that is predominantly steric. Large groups in the ortho... 

This conclusion was verified by a C NMR experiment carried out in 2h2 8o which gave a 0.05 ppm upfield shift in the resonance for the C-3 carbon relative to the carbon resonance in 2H2 0. The upfield shift in the carbon resonance establishes that the oxygen nucleophile that adds to the C-3 carbonyl group when 6 binds to pepsin must come from water. These labeling results are not consistent with the addition of the Asp-32 carboxyl group to the carbonyl group to form a covalent tetrahedral species as would occur during nucleophilic catalysis. 

Enzymatic isomerization of ds-aconitate to trans-aeon itate apparently also involves proton abstraction,165 with resonance in the anion extending into the carboxylic acid group. Its mechanism may be directly related to that of the oxosteroid isomerase. However, there are other 1,3-proton shifts in which neither a carbonyl nor a carboxyl group is present in the substrate (Eqs. 13-55,13-56). 

It should be noted that the kinetics for the human B isoenzyme are more complicated in that the pH dependence indicates that additional groups influence the rate. Studies with the isoenzyme carboxymethylated at His-200 prepared from 13C-labelled bromoacetate show that the pH dependence of the 13C NMR signal can be fitted to a curve with two pKa values of 6.0 and 9.2, but not to a curve with a single pKa. The second group could be the imidazole side-chain of His-200. Paramagnetically shifted 13C NMR resonances in the modified Co11 human carbonic anhydrase-B have been located by a novel method 498 This should allow the confirmation of an earlier postulate that the carboxymethyl carboxylate is a ligand for zinc in the modified enzyme. 

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