Amides resonance stabilization

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. 

Much of the chemical reactivity of the /8-lactam antibiotics is associated with die /i-lactam moiety. The geometry and the accompanying increased ring strain results hr very little, if any. amide-resonance stabilization leading to a marked increase in chemical reactivity when compared to a normal amide. In fact, in many instances the reactivity of the lactam carbonyl is... 

In resonance language, there are two contributing forms. Since this amide resonance stabilization would be lost if the nitrogen atom were pro-tonated, protonation is disfavored. 

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

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. 

Acylimidazoles and related amides in which the nitrogen atom is part of an aromatic ring hydrolyze much more rapidly than other amides. A major factor is the decreased resonance stabilization of the carbonyl group, which is opposed by the delocalization of the nitrogen lone pair as part of the aromatic sextet. 

Amides and ureas may react also with trifluoromethanesulfonic anhydride to give resonance-stabilized dicarbonium salts [36] (equation 34). 

In this paper Speziale and Smith 109) described experiments which led them to modify the mechanism proposed earlier 108) for the reaction of trivalent phosphorus compounds with haloamides. The first step is considered to be attack of the trivalent phosphorus compound on a chlorine atom of the halo amide (132) to produce a resonance-stabilized enolate ion (133). This is reasonable since under conditions where the trichloroamide... 

Such one-center enhancement effects can be illustrated by formamide 5 for nb—>7Ta (3.109c) interactions. As shown in Table 3.19, the n — -7tco interaction of 5 leads to strong conjugative stabilization (59.8 kcal mol-1) and reduced C—O bond order (1.732), the famous amide resonance of peptide chemistry ... 

Pre-eminent amongst examples is the case of amides, which do not show the typical basicity of amines. Acetamide, for example, has pATa — 1.4, compared with a 10.7 in the case of ethylamine. This reluctance to protonate on nitrogen is caused by delocalization in the neutral amide, in which the nitrogen lone pair is able to overlap into the n system. This type of resonance stabilization would not be possible with nitrogen protonated, since the lone pair is already involved in the protonation process. Indeed, if amides do act as bases, then protonation occurs on oxygen, not on nitrogen. Resonance stabilization is still possible in the D-protonated amide, whereas it is not possible in the A-protonated amide. Note that resonance stabilization makes the D-protonated amide somewhat less acidic than the hydronium ion (pATa — 1.7) the amide oxygen is more basic than water. 

It system, thus creating resonance stabilization in the neutral amide. This effect also diminishes the reactivity of the carbonyl towards nucleophilic attack, since the resonance contribution actually means less carbonyl character and more carbon-nitrogen double bond character. 

Although protonation does not occur on nitrogen in an amide, protonation can occur on the carbonyl oxygen, because this still allows the same type of resonance stabilization. Accordingly, acid hydrolysis of amides proceeds through nucleophilic attack of water onto the protonated carbonyl, giving a tetrahedral protonated intermediate. 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

Note that acids, and primary and secondary amides cannot be employed to generate enolate anions. With acids, the carboxylic acid group has pATa of about 3-5, so the carboxylic proton will be lost much more easily than the a-hydrogens. In primary and secondary amides, the N-H (pATa about 18) will be removed more readily than the a-hydrogens. Their acidity may be explained because of resonance stabilization of the anion. Tertiary amides might be used, however, since there are no other protons that are more acidic. 

Like amides, 2- and 4-pyridones are also very weak bases, mnch weaker than amines. Like amides, they actnally protonate on oxygen rather than nitrogen (see Section 4.5.4). This fnrther emphasizes that the nitrogen lone pair is already in nse and not available for protonation. On the other hand, the N-H can readily be deprotonated pyridones are appreciably acidic abont 11). The conjngate base benefits from considerable resonance stabilization, both via... 

Tropicamide has p Ta appropriate for a pyridine ring. The second nitrogen is part of an amide group, and is thus a very weak base. Amides are stabilized through resonance, a stabilization that is not possible in the conjugate acid. 

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