Amides, amide-imide tautomerism

Scheme 13.11 Typical synthons for amide and imide tautomeric forms of sulfonamide.

The main intermediate of the rearrangement may be a nitrilium ion (225) in some cases or an imidate (226) in others. The resulting intermediate reacts with water to produce the amide (218) after tautomerization. If other nucleophiles (Nu ) are present, they can intercept the reactive intermediates (both inter- or intra-molecularly) and several different imino-substituted derivatives (227) can be formed. These rearrangement-addition reactions will be analysed later in this chapter as they can effectively broaden the scope of the Beckmann rearrangement reaction (Sections VI.D.2 and VI.E.2). 

The ultraviolet absorption spectra of l,2,4-triazolo[4,3-a]pyrimidines have been studied. Amide-imidic add tautomerism in l,2,4-triazolo[4,3-ajpyrimidinones has also been studied using this tool [59JOC779 77HC(30)179], The spectra of the 5-oxo-l,2,4-triazolo[4,3-a]pyrimidines (158) exhibited three absorption bands at -230,260, and 310 nm (87T2497). The 7-oxo congeners (18), in contrast, revealed only one band at 230 nm (87T2497). 

Nitriles are susceptible to hydrolysis via nucleophilic attack of water on the electropositive carbon atom, especially under strongly acidic and basic conditions (Fig. 29). Nitriles hydrolyze to imidic acids, which tautomerize to amides. Amides can be hydrolyzed further to carboxylic acids, although much more slowly. Nitriles are susceptible to oxidation by peroxides under mildly basic conditions (e.g., pH 7.5-8) as has been documented in the case... 

Metal Salts.—In discussing the constitution of acet amide, (p. 146) the formation of metal salts raised the question as to the true constitution of the amide, the tautomeric hydroxy imide formula being probable in this reaction. 

In hydrolysis of a cyano group in aqueous acid, protonation of the nitrogen atom gives a cation that reacts with water to give an imidic acid (the enol of an amide). Keto-enol tautomerism of the imidic acid gives an amide. The amide is then hydrolyzed, as already described, to a carboxylic acid and an ammonium ion. 

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. 

Base-catalysed hydrolysis. The hydroxide ion attacks the nitrile carhon, followed hy protonation on the unstable nitrogen anion to generate an imidic acid. The imidic acid tautomerizes to the more stable amide via deprotonation on oxygen and protonation on nitrogen. The base-catalysed amide is converted to carboxylic acid in several steps as discussed earlier for the hydrolysis of amides. 

There are, however, a number of observations which argue against the viability of such a string of transfers. Firstly, the imidic acid resulting from the tautomerism is considerably higher in energy than the amide. Theoretical and experimental data provide an estimate of an 11-12 kcal/mol energy difference in formamide. The tautomeric equilibrium constant is only some The proton transfer would be impossibly slow it would take more... 

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). 

Amidrazones of types A and B, in which R = H, are incapable of tautomerism. When tautomerism is possible (A B, R1 = H), the terms amide hydrazone and hydrazide imide cannot be strictly applied. Hence, the term amidrazone is used for all compounds with structure A, and is the least ambiguous (70CRV151). 

The infrared absorption spectrum of sulfacetamide sodium has been determined in KBr disc (4). The principal peaks appear at 825, 1090,1145,1264,1552,1600 cm 1. The infrared stretching frequencies of the amino group have been used to calculate the force constant, the band angle and the "S" character of the nitrogen orbitals of the N-H band (23,24). Infrared measurements of sulfonamides have been performed to study the imide-amide tautomerism (25) and to see if there is any change in the electronegativity of the SO2 group (26,27). Sulfacetamide in eye-drops and ointments has been identified by attenuated total reflectance (ATR) infrared spectra (28). 

Mateo-Marti and Pradier investigated the chemical modifications occurring within a tripeptide molecule (Glu-Pro-Glu IGF), when exposed to the influence of UV irradiation. The authors described the successful inclusion of the IGF molecule in an argon matrix, followed by the in situ UV irradiation of the sample and subsequent characterization of the compound photo-reactivity. The studies have been performed by combining, Fourier-transform reflexion absorption spectroscopy (FT-IRRAS) and X-ray photoelectron spectroscopy (XPS). The comparison of the IR spectra of the isolated oligopeptide in an argon matrix obtained before and after UV irradiation, revealed significant differences that could be associated either to a partial deprotonation of the molecule or to a tautomeric conversion of amide bonds to imide ones. XPS analyses undoubtedly confirmed the second hypothesis (amido-imido tautomerism Fig. 22). 

The mechanism of nitrile hydrolysis involves acid or base promoted addition of water across the triple bond. This gives an intermediate imidate that tautomerizes to an amide. The amide is then hydrolyzed to the carboxylic acid. The addition of water to the nitrile resembles the hydration of an alkyne (eq. 3.52). The oxygen of water behaves as a nucleophile and bonds to the electrophilic carbon of the nitrile. Amide hydrolysis will be discussed in Section 10.20. 

Hydrolysis of a cyano group in aqueous base involves initial formation of the anion of an imidic acid, which, after proton transfer from water, undergoes keto-enol tautomerism to give an amide. The amide is then hydrolyzed by aqueous base, as we saw earlier, to the carboxylate anion and ammonia. 

Step 3 Keto-enol tautomerism. Tautomerism of the imidic acid gives the amide. 

In base, the mechanism involves an initial attack of HO" on the nitrile C atom to form the anion of an imidic acid, which acquires a proton to give an imidic ion intermediate that tautomerizes to an amide, and the rest proceeds the same as for amide hydrolysis in base. 

We next study water-assisted (relayed) proton transfer in formamide, comparing with a forced proton transfer within formamide in gas phase (Fig. 7.10), which are also associated with the tautomerization. We start from the enol (imidic acid) form HO-CH=NH and track the transfer process to the keto (amide) form 0=CH-NH2. We first survey the above very basic puzzles with this system, identifying that this is indeed a proton... 

Loss of a proton and tautomerization. The conjugate acid of the imidic acid loses a proton, and the resulting imidic acid tautomerizes to give an amide. The amide continues to react by the mechanism of acid-catalyzed amide hydrolysis we discussed above. 

In the base-catalyzed hydration of a nitrile, the first step of the process is nucleophilic attack of hydroxide at the electrophihc carbon atom. Subsequent protonation of nitrogen by water yields an imidic acid. The imidic acid tautomerizes to give an amide that hydrolyzes to yield the carboxylic acid. 

Explain why the tautomeric equilibrium between an imidic acid and an amide lies on the side of the amide. 

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