Tautomerization amide-enol

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>. 

Simple enols stabilized by bulky aryl groups have been reviewed.131 Amide enols, tip2C=C(OH)NR1R2 (tip = 2,4,6-triisopropylphenyl), can be generated by reaction of amines with ditipyl ketene, are observable by NMR, and slowly tautomerize. Vinyl alcohols with two or three bulky aryls have propeller conformations and are chiral, but are not easily resolved. 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

Tautomerization of the hydroxyimine yields an amide in a reaction analgous to the tautomerization of an enol to give a ketone. 

Amination of ketene has been studied by ab initio methods.Reactions of ammonia, its dimer, and its (mono)hydrate with ketene have been calculated and compared with earlier smdies of ammonia (at lower levels of theory), of water, and of water dimer. In general, the results favour initial addition of ammonia to the C=0 bond (giving the enol amide), as against addition to the C=C bond (which gives the amide directly). Amide formation is compared with the corresponding hydration reaction where enol acid and acid are the alternative immediate products. Most of the reactions, i.e. both additions and tautomerizations, are suggested to involve cyclic six-membered transition states. 

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). 

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. 

It is important to distinguish tautomerism from resonance, a term used to indicate that the properties of a given molecule cannot be represented by a single valence structure but can be represented as a hybrid of two or more structures in which all the nuclei remain in the same places. Only bonding electrons move to convert one resonance form into another. Examples are the enolate anion, which can be thought of as a hybrid of structures A and B, and the amide linkage, which can be represented by a similar pair of resonance forms. 

Aldehydes, ketones, carboxylic esters, carboxylic amides, imines and N,A-disubstiluted hydrazones react as electrophiles at their s/ 2-hybridized carbon atoms. These compounds also become nucleophiles, if they contain an H atom in the a-position relative to their C=0 or C=N bonds. This is because they can undergo tautomerization to the corresponding enol as seen in Chapter 12. They are also C,H-acidic at this position, i.e., the H atom in the a-position can be removed with a base (Figure 13.1). The deprotonation forms the conjugate bases of these substrates, which are called enolates. The conjugate bases of imines and hydrazones are called aza enolates. The reactions discussed in this chapter all proceed via enolates. 

This compound is a tautomer of an amide. Tautomerization occurs in the same manner as was the case for the conversion of an enol to its carbonyl tautomer. 

Reprotonation occurs on the nitrogen to produce the amide. As was the case with the carbonyl—enol tautomerization, the stability of the carbon—oxygen double bond causes the amide tautomer to be favored at equilibrium. 

Tautomerization of the enol to a ketone, addition of water, and another tautomerization to an amide complete the mechanism. Notice here that a nitrogen has been added to a tertiary centre— this is not an easy result to accomplish and it is worth noting that conjugate addition is a good way to make bonds to crowded centres. 

Alcohols can be added to nitriles in an entirely different manner from that of reaction 16-9. In this reaction, the alcohol is converted by a strong acid to a carbo-cation, which is attacked by the nucleophilic nitrogen atom to give 117. Subsequent addition of water to the electrophilic carbon atom leads to the enol form of the amide (see 118), which tautomerizes (p. 98) to the V-alkyl amide. 

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