Carboxylic acid derivatives resonance

C NMR The C NMR spectra of carboxylic acid derivatives like the spectra of carboxylic acids themselves are characterized by a low field resonance for the carbonyl... 

Another example of the effect of resonance is in the relative acidity of carboxylic acids as compared to alcohols. Carboxylic acids derived from saturated hydrocarbons have ipK values near 5, whereas saturated alcohols have pA values in the range 16-18. This implies that the carboxylate anion can accept negative charge more readily than an oxygen on a saturated carbon chain. This can be explained in terms of stabilization of the negative charge by resonance, ... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

This is a consequence of delocalization, with resonance stabilization being possible when the carbonyl oxygen is protonated, but not possible should the OR oxygen become protonated. This additional resonance stabilization is not pertinent to aldehydes and ketones, which are thus less basic than the carboxylic acid derivatives. However, these oxygen derivatives are still very weak bases, and are only protonated in the presence of strong acids. 

The reaction involves the transfer of an electron from the alkali metal to naphthalene. The radical nature of the anion-radical has been established from electron spin resonance spectroscopy and the carbanion nature by their reaction with carbon dioxide to form the carboxylic acid derivative. The equilibrium in Eq. 5-65 depends on the electron affinity of the hydrocarbon and the donor properties of the solvent. Biphenyl is less useful than naphthalene since its equilibrium is far less toward the anion-radical than for naphthalene. Anthracene is also less useful even though it easily forms the anion-radical. The anthracene anion-radical is too stable to initiate polymerization. Polar solvents are needed to stabilize the anion-radical, primarily via solvation of the cation. Sodium naphthalene is formed quantitatively in tetrahy-drofuran (THF), but dilution with hydrocarbons results in precipitation of sodium and regeneration of naphthalene. For the less electropositive alkaline-earth metals, an even more polar solent than THF [e.g., hexamethylphosphoramide (HMPA)] is needed. 

Tab. 6.2 Energy Gain through Resonance in Nonprotonated and Protonated Carboxylic Acid Derivatives...

Amides are carboxylic acid derivatives. The amide group is recognized by the nitrogen connected to the carbonyl group. Amides are neutral compounds the electrons are delocalized into the carbonyl (resonance) and thus, are not available to bond to a hydrogen ion. 

Consider the case of an acyl chloride. The chlorine is an inductive electron with-drawer and a resonance electron donor. As we saw in Chapter 17, the inductive effect is stronger. (Recall that chlorine is not a very strong resonance electron donor because the long C—Cl bond and the size difference between the 3p AO on the Cl and the 2p AO on the C result in poor overlap of these orbitals.) In addition, chloride anion is a very weak base. Overall, acyl chlorides are the most reactive of the carboxylic acid derivatives discussed here and are the least favored at equilibrium. 

Although the rate of reaction of a carboxylic acid derivative depends on the inductive and resonance effects of the leaving group and the position of the equilibrium de-... 

Amides Simple amides have much lower carbonyl stretching frequencies than the other carboxylic acid derivatives, absorbing around 1640 to 1680 cm-1 (often a close doublet). This low-frequency absorption agrees with the resonance picture of the amide. The C=0 bond of the amide carbonyl is somewhat less than a full double bond. Because it is not as strong as the C=0 bond in a simple ketone or carboxylic acid, the amide C=0 has a lower stretching frequency. 

Because carboxylic acid derivatives (RCOZ) all contain an atom Z with a nonbonded electron pair, three resonance structures can be drawn for RCOZ, compared to just two for aldehydes and ketones (Section 20.1). These three resonance structures stabilize RCOZ by delocalizing electron density. In fact, the more resonance structures 2 and 3 contribute to the resonance hybrid, the more stable RCOZ is. 

Thus, the carbonyl group of an acid chloride and anhydride, which are least stabilized by resonance, absorb at higher frequency than the carbonyl group of an amide, which is more stabilized by resonance. Table 22.4 lists specific values for the carbonyl absorptions of the carboxylic acid derivatives. 

NMR The NMR spectra of carboxylic acid derivatives, like the spectra of carboxylic acids themselves, are characterized by a low-field resonance for the carbonyl carbon in the range 8 160-180 ppm. The carbonyl carbons of carboxylic acid derivatives are more shielded than those of aldehydes and ketones, but less shielded than the sp -hybridized carbons of alkenes and arenes. 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

At this point we want to consider the relative reactivity of carboxylic acid derivatives and other carbonyl compounds in general terms. We return to the subject in more detail in Chapter 7. Let us first examine some of the salient structural features of the carbonyl compounds. The strong polarity of the C=0 bond is the origin of its reactivity toward nucleophiles. The bond dipole of the C-X bond would be expected increase carbonyl reactivity as the group X becomes more electronegative. There is another powerful effect exerted by the group X, which is resonance electron donation. 

Second, the weaker the basicity of Y, the smaller is the contribution from the resonance contributor with a positive charge on Y (Section 17.2) the less the carboxylic acid derivative is stabilized by electron delocalization, the more reactive it will be. 

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