Resonance in amides

Resonance in Amides, Carboxylic Acids, and Related Compounds... 

An interesting controversy concerning the role of resonance in amides, carboxylic acids, and other species containing tt systems developed in the past five years. Electron populations played a central role in this controversy. 

Other examples of the use of populations to refute the contribution of resonance in ground state molecules include the acidity of nitrous and nitric acidio and the rotational surfaces of nitramide O and butadiene.Experimental support for the lack of resonance in amides was reported by Brown and co-workers, who find that the rate of amide hydrolysis correlates with the hybridization on... 

A number of objections to this concept of minimal resonance in amides and carboxylic acids have appeared. Exner ° argued that isodesmic reactions indicate that the carboxylate anion is much more stable than the enolate anion, reflecting the resonance in the former. Thomas rebutted this argument by... 

Although an analogous schane can be written for acetamide, recent ab initio calculations have questioned the importance of resonance in amides, i.e. 17 17, ... 

Figure 2-51. a) The rotational barrier in amides can only be explained by VB representation using two resonance structures, b) RAMSES accounts for the (albeit partial) conjugation between the carbonyl double bond and the lone pair on the nitrogen atom. 

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 most common amides cleavage is quite difficult, but in the case of an aziridine (which exhibited reduced participation significantly in amide resonance because of the nonplanar amide moiety ) hydrolysis is much simpler, as shown in the following illustration ... 

In contrast with amines, amides (RCONH ) are nonbasic. Amides don t undergo substantial protonation by aqueous acids, and they are poor nucleophiles. The main reason for this difference in basicity between amines and amides is that an amide is stabilized by delocalization of the nitrogen lone-pair electrons through orbital overlap with the carbonyl group. In resonance terms, amides are more stable and less reactive than amines because they are hybrids of two resonance forms. This amide resonance stabilization is lost when the nitrogen atom is protonated, so protonation is disfavored. Electrostatic potential maps show clearly the decreased electron density on the amide nitrogen. 

Lactams are generally more reactive toward nucleophiles than are normal amides. The ease of the nucleophilic attack on the lactam carbonyl group is usually attributed to either relief of strain upon opening the ring [68], or to a reduction in the usual amide resonance due to nonplanarity of the bicyclic system [69]. However, the evidence to support unusual strain in the ring or reduced amide resonance in /3-lactam antibiotics is ambiguous. 

Page demonstrated in 1992 in a critical analysis [73] that bicyclic /3-lac-tam antibiotics do not exhibit exceptional chemical reactivity. He concluded that neither kinetic nor ground-state effects indicate a significant degree of inhibition of amide resonance in penicillins and cephalosporins [72] [74], Indeed, in comparison to normal amides, the /3-lactam N-atom does not exhibit any enhanced ability to donate its electron pair to either protons or metal ions [75] [76],... 

The H- and C-NMR spectroscopic data support the proposed primary structure of poly(Lys-25). The amide carbonyl resonances are particularly informative as these signals are well resolved in the C-NMR spectrum of poly(Lys-25) (Figure 4). An amide carbonyl resonance is observed at 174.9 ppm for poly(Lys-25) that does not appear in the spectrum of poly(Val-Pro-Gly-Val-Gly) [13]. The position and relative intensity of this resonance are consistent with a lysine amide carbonyl group within a peptide bond [14]. Moreover, the resonances of the amide carbonyl groups for other residues in the pentapeptide repeat are split due to the substitution of a lysine residue at position 4 in every fifth pentapeptide in Lys-25. In addition, the absence of splitting in amide carbonyl group of valine in position 4 (174.5 ppm) supports this assignment, as this residue is replaced by lysine in the fifth pentapeptide of the Lys-25 repeat. The presence of other resonances attributable to the lysine residue can be detected in the H- and C-NMR spectra of the Lys-25 polymer at levels commensurate with its... 

Figure 4 Detail of the amide carbonyl resonances in the C-NMR spectrum (100 MHz) of poly (Lys-25) in 70% H2O/30% D2O solution. The spectrum was recorded on a Varian INOVA 400 NMR spectrometer. Chemical shifts were referenced to external tetramethylsilane.

Note that we can write a similar resonance picture for esters, and we shall actually need to invoke this when we discuss enolate anions (see Section 10.7). However, electron donation from oxygen is not as effective as from the less electronegative nitrogen. We shall also see that this resonance effect in amides has other consequences, such as increased acidity of the amide hydrogens (see Section 10.7) and stereochemical aspects of peptides and proteins (see Section 13.3). In addition, the amide derivatives have... 

In amides, the lone electron pair on the nitrogen atom promotes resonance stabilization of the carbonyl region (see Figure 9-14). This stabilization is important not only to amides, but also to the secondary structure of proteins. 

Limited carbonyl NMR data are available for these anomeric amides. However, carbonyl shifts for hydrazines 217 and 218 were on average 3 ppm higher than their hydroxamic ester precursors. This reflects a higher degree of residual amide resonance in the hydrazines relative to A-acyloxy-iV-alkoxyamides where the difference was closer to 8.0 ppm. As reported for A-acyloxy-A-alkoxyamides (see Section IV.B.2), analysis of variance in the hydrazine and hydroxamic ester shifts indicates that substituents affect the hydroxamic ester carbonyl shifts ( 2.6) more than those of the hydrazines ( 1.3 ppm). 

At all levels of theory, the N-acetyl group of N-acetyl-N-arylnitrenium ions is rotated out of the plane of the aromatic ring, although to different extents." The N-acetyl group destabilizes the ion by ca. 20 kcal/mol relative to an N-methyl substituent in comparison with the neutral amide and amine precursors. This destabilization was attributed by Ford and Herman to loss of resonance in the amide precursor on going to the nitrenium ion, not to inductive destabilization of the ion by the acyl group. 

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