Carboxylic acid derivatives relative reactivities

What structural features are responsible for the reactivity order of carboxylic acid derivatives Like the other carbonyl containing compounds that we ve studied they all have a planar arrangement of bonds to the carbonyl group Thus all are about the same in offering relatively unhindered access to the approach of a nucleophile They differ m the degree to which the atom attached to the carbonyl group can stabilize the carbonyl group by electron donation... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

The Vcirious carboxylic acid derivatives vary in their reactivity (stability of the leaving group). Acid chlorides, for example, are more reactive than anhydrides (don t leave as easily). A summciry of the relative reactivities appears in Figure 12-32. 

A direct synthetic route to 4//-7-hydroxybcnzo[ ]tellurin-4-ones 138 involves acid-promoted dehydration of the corresponding (Z)-unsaturated carboxylic acid derivatives 137 (Scheme 14) <19980M3588>. These precursors can be readily prepared by a metallation-telluration sequence. Previous attempts to prepare molecules of this type, particularly the telluroflavones (R = Ph), were unsuccessful due to the unexpected reactivity of the C-Te bond relative to the C-Se and C-S bonds. 

Hlectronically, we find that strongly polarized acyl compounds react more readily than less polar ones. I hus, add chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic acid derivatives indicate the differences by the relative blueness on the C=0 carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

Relative Stability and Reactivity of Carboxylic Acid Derivatives... 

Modification of the products that resulted from the aza-annulation of tetrasubstituted enamine substrates with acrylate derivatives was very limited. The aza-annulation of benzyl ester 496 with the mixed anhydride, a mixture (497) preformed from EtC CCl and sodium acrylate, provided a route to 498 in >98 2 diastereoselectivity (eq. 100), which allowed access to the carboxylic acid derivative 499 through catalytic hydrogenation.1 Further elaboration of either the ester or the acid derivative was unsuccessful, possibly due to the steric congestion around the reactive functionality. Extended hydrogenation did not reduce the enamine functionality, as observed in related substrates, and 498 was relatively stable to acidic hydrolysis conditions. In addition, DCC (N,N -dicyclohexylcarbodiimide) coupling of acid 499 with either benzyl amine or glycine ethyl ester was unsuccessful. 

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. 

Relative Reactivities, Structures, and Spectra of Carboxylic Acid Derivatives Comparisons of physical properties. 

Fig. Relative reactivity of carboxylic acid derivatives. Electronic Factors...

The relative reactivity of carboxylic acid derivatives was discussed in Chapter 10. 

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