Amide/imidate tautomers

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. 

Acylation of l,2,4-triazolo[l,5-c]quiiiazoliii-5-oiie (141) with ethyl chlo-roformate occurred at N6 to afford the 6-ethoxycarboiiyl derivative 142 (75CB3799) (Scheme 55). Tliis result indicates that the amide tautomer (lactam tautomer) 141 prevailed over the corresponding imidic acid tautomer (lactim tautomer). 

Tlie infrared spectra revealed the dominance of the 2-oxo (153) and 5-0X0 (157) structures (amide or lactam tautomers) over the 2-hydroxy (154) and the 5-hydroxy (192) structures (imidic acid or lactim tautomers)... 

All three amides are evidently mixtures of tautomers. It should be noted that the nitrogen atom in the imide form is sterically unhindered and sufficiently basic to provoke deprotonation of silylated AN... 

Since the second solvent pair fall within the poor hydrogen bonding group of solvents, increased basicity of the organic base in these solvents would be consistent with the observed behavior. Based on the model compound studies, indications are that the base-catalyzed imidization process may involve a two-step mechanism, Jee Scheme 23. The first step corresponds to the complete or partial proton abstraction from the amide group with the formation of an iminolate anion. Since this iminolate anion has two possible tautomers, the reaction can proceed in a split reaction path to either an isoimide- or imide-type intermediate. Although isoimide model reactions indicate an extremely fast isomerization to the imide under the conditions employed for base-catalysis, all indications to date are that it is not an intermediate in the base-catalyzed imidization of amic alkyl esters. 

Imidic acid (40) is the lactim tautomer of an acid amide (39 lactam form). Although no substantiated claim has been put forward for the isolation of free imidic acids, imidates (41) (also... 

The amide form is the more stable tautomer, having a C=0 and an N-H bond. The imidic acid tautomer is the less stable form, having a C=N and an O-H bond. ... 

The imidic acid and amide tautomers are interconverted by treating with acid or base, analogous to the keto-enol tautomers of other carbonyl compounds. In fact, the two amide tautomers are exactly the same as keto-enol tautomers except that a nitrogen atom replaces a carbon atom bonded to the carbonyl group. 

The mechanism of nitrile hydrolysis in both acid and base consists of three parts [1] nucleophilic addition of H2O or OH to form the imidic acid tautomer [2] tautomerization to form the amide, and [3] hydrolysis of the amide to form RCOOH or RCOO. The mechanism is shown for the basic hydrolysis of RCN to RCOO (Mechanism 22.11). 

H and NMR measurements (73JA4761, 73JHC431 76JA4736 84MI10) indicated the predominance of the Nl-H tautomer (386) over the N2-H (392) tautomer for formycin and the amide form (387) over the imidic acid form (393) for formycin B. 

Ambident Nucleophiles. Amides and related functional groups can be alkylated on oxygen or nitrogen and, as has been noted already, alkylation on carbonyl oxygen normally predominates. In the case of carbamates, 0-alkylation by Me0S02F can be faster, but W-alkylation predominates at equilibrium. It has been noted that methylation of secondary amides and thioamides occurs at the protonless heteroatom in the major tautomer. The ionic products of these reactions can be deprotonated to give synthetically useful products, e.g. imidates, but excess Me0S02F should be removed before treatment with base. ... 

Hydrolysis of a Nitrile (Section 18.4E) Either acid or base is required in an amoimt equivalent to that of the nitrile. In acid, the mechanism involves an initial protonation of the nitrile N atom, followed by attack by water to give an imidic acid that tautomer-izes to give an amide, and the rest proceeds the same as for amide hydrolysis in acid. 

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