Tautomerism, keto-enol amides

An investigation of keto-enol tautomerism for perfluorinated keto-enol systems was undertaken. N-methylpyrrolidone (NMP) catalyzes equilibration of the keto and enol forms, but if used in more than trace amounts, it drives the equilibrium strongly toward enol because of hydrogen bonding to the amide. The enol is much more thermodynamically stable than its ketone, and it was found that in mildly Lewis basic solvents, such as ether, THE, acetonitrile, and NMP, the enohzation equilibrium lies too far right to allow detection of ketone (Correa et al., 1994). 

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. 

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. 

Fig. 4.3 (5/J,S/J-)Lyseigic acid amide/t5/J,5y-lisolysergic acid amide equilibrium in, e.g., aqueous solution due to keto-enol tautomerism...

A typical example of tautomerism is represented by the equilibrium between hydroxypyrazine 4 or 7 and 2(1//)-pyrazinone 5 or 8, in which the latter keto form predominates over the hydroxyl or enol form. A similar situation exists in hydroxylquinoxaline 6. The tautomeric equilibrium, however, is susceptible to the additional substituents. For example, 6-amino-2(l//)-pyrazinone 8 (R = Me, = Bn, R = NH2) has been shown to predominate over the hydroxyl form 7 <1993JOC7542>. On the contrary, 6-methoxy-2-hydroxypyrazines 7 (R = Me, R = Ph, R = OMe) exist in the hydroxyl form rather than as the tautomeric amide <1997J(P1)3167>, and these examples have a predominance of the hydroxyl form parallel the isomeric 5-methoxy-2-hydroxypyrazines as well as the chloro-hydroxypyrazine field <1996CHEG-II(6)233>. 

NMR spectroscopy has also been a useful probe for the assignment of tautomeric structures. For example, compounds (20) and (21) can exist in the tautomeric enol forms (22) and (23), respectively. 1H NMR spectroscopy favors the keto form (20) over the enol form (22) and the enol form (23) over the amide form (21), in solution (78AHC(22)183). Few compounds with substituents capable of tautomeric existence are known or have been studied in all the series and therefore no specific predictions can be made regarding the predominance of one tautomer versus the other. 

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... 

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