2 -Aminopyridines, tautomerism

This method is not applicable if the spectra of the potentially tautomeric compound and both alkylated derivatives are very similar, e.g., it is not suited to an investigation of the tautomerism of 4-aminopyridine 1-oxide (Fig. 3). A further limitation is that often only qualitative conclusions can be drawn because no contribution from the spectrum of the minor constituent can be found in the spectrum of the tautomeric compound. It should also be noted that, un-... 

Dipole moment data have provided valuable information for the study of the tautomerism of compounds such as isonicotinic acid, pyrid-4-one, and ethyl acetoacetate, However, this method must be used with discretion since it can lead to inconclusive results. Thus, the fact that 4-aminopyridine has a higher dipole moment than the algebraic sum of the dipole moments of pyridine and aniline was originally interpreted as proof that structure 54 exists with a strong contribution from 36, and it was stated that 55 w ould have a very low moment. Later, Angyal and AngyaF pointed out that the... 

The ultraviolet spectra of many substituted aminopyridines were reported in 1959 with rather vague reference to their tautomerism however, the gross structure assigned to some of the sulfonamido compounds has been criticized. ... 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

Aminopyridines are also potentially tautomeric with corresponding imino forms. 

However, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino tautomers - indeed, we have just seen 2-aminopyridine as a product of the Chichibabin reaction. Which tautomer is preferred for hydroxy and amino heterocycles is not always easily explained but, as a generalization, we find that the oxygen derivatives exist as carbonyl tautomers and amino heterocycles favour the amino tautomers. At this stage, we should just register the potential for tautomerism in aminopyridines we shall see important examples with other heterocycles (see Section 11.6.2). 

We have seen that 2- and 4-hydroxypyridines exist primarily in their tautomeric amide-like pyridone forms (see Section 11.4.3). This preference over the phenolic tautomer was related to these compounds still retaining their aromatic character, with further stabilization from the carbonyl group. 3-Hydroxypyridine cannot benefit from this additional stabilization. In contrast, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino... 

All three aminopyridines are known, but although the 2-and 4-aminopyridines are potentially tautomeric with imino forms, they seem to exist as the amino tautomers (Scheme 2.27). 

As discussed previously (Section 2.04.4.1), the tautomeric equilibrium in aminopyridines and their benzo analogues lies well in favor of the amino form, whether in solid or gas phase, or in inert or polar solvents. The evidence has been well documented and discussed (76AHC(Sl)7l). Thus, in the respective examples of tautomeric equilibria (224) through (231), the favored form is on the left hand side in all cases. 

The piperidino compound (163 R R" = —(CH2)5—) is easily hydrolyzed,110 and the anilino compound (163 R = Ph R" = H) cannot be prepared by this route.111 A number of these compounds have been prepared by the alternative route 160a - 164 - 163.112 The reaction conditions were modified in more recent studies.113 Robertson identified 163 (R = 2-pyridyl R" = H) as the unexpected product of the reaction between 2-nitrophenylpropiolic acid and 2-aminopyridine. Further studies are needed to clarify these conflicting, and in some cases tentative, reports. The tautomerism of these compounds (163 R = aryl R" = H) is worthy of further study111 (cf. Section II,A,4). Recently, a study of the tautomerism of the carbazide derivatives (165) has been made both tautomers (163, 165) were reportedly identified.114... 

NMR longitudinal relaxation times can be used for determination of the site of protonation in polyfunctional acids and bases (93JCS(P2)283). Thus, the 14N NMR spectrum of 4-aminopyridine shows clearly from the sharpening of the signal for the ring nitrogen that protonation has occurred here. This procedure is an important innovation in the elucidation of heterocyclic tautomeric structures, especially for the cases of fast exchange. 

The structure of the reaction product of 2-aminopyridine and diethyl malonate, described by Chichibabin as 2,4-dioxo-3,4-dihydro-2//-pyrido-[l,2-<7]pyrimidine,96 was first questioned by Snyder and Robison253 on the basis of the high melting point and poor solubility of the compound. They suggested the tautomeric 2-hydroxy-4-oxo-4H-pyrido[l,2-a]pyrimidine structure. The problem was solved by Katritzky and Waring273 who compared the UV spectrum of the product with that of fixed tautomers and found that the product may best be described as anhydro- 2-hydroxy-4-oxo-4/f-pyrido[l,2- ]pyrimidinium)hydroxide (63). Because of the chemical behavior of these compounds, however, the contribution of other mesomeric forms to the structure has also been considered.122 Thus, PPP-SCF quantum chemical calculations suggest that 1,4-dipolar cycloadditions to the C-3 and C-9a atoms are to be expected.352 This type of reaction does in fact occur (see Section III,C,10). Katritzky and Waring273 estimated the ratio of the mesomeric betaine (63 R = H) and the 2-hydroxy-4-oxo tautomers to be about 20 1. 

The ethyl (2-pyridylaminomethylene)cyanoacetates 161, prepared from the appropriate 2-aminopyridine and ethyl ethoxymethylenecyanoacetate in refluxing dioxane in the presence of triethylamine, exhibited a triple tautomerism among the E and Z isomers of 161 (E and Z) and the closed-... 

The solvent, temperature, and substituent (R and R1) -dependent ring-chain tautomerism of 2-pyridylaminomethylenemalononitriles (167 168) was studied (86JOC2988). 2-Pyridylaminomethylenemalo-nonitriles were prepared in the reaction of 2-aminopyridines and 2-(l-ethoxyalkylidene)malononitrile in ethanol at room temperature or in a melt at 120°C, and in a one-pot reaction, starting from 2-aminopyridines, a triethyl orthoester, and malononitrile at 110°C for 10 minutes. The content of the equilibrium mixture of 2-pyridylaminomethylenemalononitrile 167 (R = R1 = H) is shown in Table X. Elevation of the temperature increased the proportion of the chain tautomer. The ratio between the two tautomeric forms 167 and 168 is influenced primarily by the steric properties of substituents R and R1 in positions 6(6) and 3(9), respectively,... 

The relationships between tautomeric equilibrium constants and intramolecular hydrogen bonds (IMHB) are well documented. As expected, an IMHB stabilizes the tautomer that presents it in comparison with other tautomers without IMHB. On the other hand, information about the effect of intermolecular hydrogen bonds on the thermodynamic aspect of tautomerism is scarce. These HBs are of paramount importance in the solid state in solution, the situation is more complicated because there are several possible associations that exist in dynamic equilibrium. For this reason we devoted a theoretical paper to this question, studying homo- and heterodimers of 2-pyridone (63, 64, 65) and 2-aminopyridines (66, 67, 68) [84], In the case of pyridone the most stable dimer is 63 for 2-aminopyridine, it depends on the nature of R. 

The tautomerism of 2-pyridones 25 that are favored over 2-hydroxypyridines 24 (and conversely, 2-aminopyridines 26 that are favored over 2-imino-derivatives 27) plays a central role in the chemistry and biochemistry of all azines [146-148], A comparison between A-methyl-2-pyridone and 2-methoxypyridine shows that the magnetic susceptibility of the former is about 20% greater than that of the latter [149],... 

Like the tautomerism of the hydroxy- and aminopyridines (Sections 3.2.3.7.1 and 3.2.3.5.5), there are alternative tautomeric alkylidene forms of the 2- and 4-alkylpyridines (e.g., 647 for 2-picoline). Although the proportion of alkylidene form at equilibrium is very small (discussed in Section 2.2.5.1.2), it can be important as a reactive intermediate (see above). 

A study of the tautomerism between 49 and 50s 5, which are synthesized from the condensation of 3-aminopyridines and isobutyraldehyde, shows that the equilibrium position varies drastically according to the substituents and their position on the pyridine ring. With a nitro or an ethoxy group at position-2, the equilibrium lies well to the... 

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