Nitrogen tautomerization

Also, (5-phenyl-l,3,4-oxadiazol-2-yl)-7-hydroxycoumarin is a tautomeric compound. In dilute solutions it is almost totally present in its protonated nitrogen tautomeric form. The deprotonation is a reversible process (Scheme 2). Quantum-mechanical calculations were carried out and correlated with experimental observations <2000SAA1773>. 

The NOB of both nitrogens (tautomeric equilibrium) is deduced on titration of the Imidazole ring of histidine due to the loss of a proton. However no bell-shape curve of the NOE values of both imidazole nitrogens in dependence of pH could be observed. 

Since nitrogen tautomerism in 15 resembles in formal structure that of an amidine such as 14 it might be expected to follow similar rules. However, it does not. 

Dissolve ca. 0 2 g. of product (I) in cold ethanol, and add with shaking 1-2 drops of dilute sulphuric acid. A deep purple coloration appears at once. This shows that salt formation has occurred on the quinoline nitrogen atom to form the cation (Ha), which will form a resonance hybrid with the quinonoid form tils). [Note that the forms (IIa) and (11b) differ only in electron position, and they are not therefore tautomeric.] If, hoAvever, salt formation had occurred on the dimethylaniino group to give the cation (III), thrs charge separiition could not occur, and the deep colour would be absent. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

When the lone electron pair is protonated, the nitrogen chemical shift moves by ca. 100 p.p.m, to higher field. Large upheld shifts are also found when a compound exists in a tautomeric form with a proton on the nitrogen. The nitrogen NMR spectrum is often of considerable value in studies of tautomerism of this type. 

The tautomerism of a methyl group a or y to a ring nitrogen (78 79) is still less... 

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. 

For the NH azoles (Table 3), the two tautomeric forms are usually rapidly equilibrating on the NMR timescale (except for triazole in HMPT). The iV-methyl azoles (Table 4) are fixed chemical shifts are shifted downfield by adjacent nitrogen atoms, but more by a pyridine-like nitrogen than by a pyrrole-like iV-methyl group. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as examples of other possible structures. A detailed investigation of this system disclosed that in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) (150) or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) (149) or (150). 

Since the electrophilic reagent attacks the multiply-bonded nitrogen atom, as shown for (68) and (69), the orientation of the reaction product is related to the tautomeric structure of the starting material. However, any conclusion regarding tautomeric equilibria from chemical reactivity can be misleading since a minor component can react preferentially and then be continually replenished by isomerization of the major component. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Dihydroazoles can exist in at least three forms (cf. Section 4.01.1.3), which in the absence of substituents are tautomeric with each other. The forms in which there is no hydrogen on at least one ring nitrogen normally predominate because imines are generally more stable than vinylamines in aliphatic chemistry. Thus for dihydropyrazoles the stability order is A" (hydrazone) (288) > A (azo) (289) >A (enehydrazine) (290). 

For )V-unsubstituted pyrazoles the tautomeric proton was generally located without ambiguity. 3-Substituted tautomers were favoured in the solid state (45), (46) and (48) (Table 5). For the pyrazolyltriazole (47) the authors (77JHC65) concluded that the X-ray analysis indicates that the proton on the pyrazole ring populates either nitrogen atom to... 

Often electrophilic reagents can attack both nitrogen atoms of the mesomeric pyrazolate and indazolate anions. In this case there is no simple relationship between the tautomeric constant and the product composition. 

Hydroxy and mercapto substituents at the 3- and 5-positions can also exist in tautomeric forms (see Section 4.01.5.2) and can be alkylated at either the substituent or the ring nitrogen atom. 3-Methoxy groups are not replaced by nucleophiles, but both 3- and 5-alkylthio groups react readily, as does 3-methoxy-l,2-benzisothiazole. Alkylthio compounds can be oxidized to sulfoxides and sulfones, and the latter readily undergo nucleophilic replacement. All the hydroxy compounds react with phosphorus pentachloride to give the chloro derivatives. 

Any heterocycle containing the OCH=CH moiety can in principle extrude the superfluous fragment and form oxirene, as illustrated for a five-membered ring in Scheme 105. Probably the most propitious AB fragment would be nitrogen, but the required 1,2,3-oxadiazole (123) is unknown (see Chapter 4.21), probably because of ready valence tautomerization to diazoethanal (Scheme 106) (this approach has been spectacularly successful with the sulfur analogue of (2) (8UA486)). The use of (123) as an oxirene precursor is thus closely linked to the important diazo ketone decompositions discussed in Section 5.05.6.3.4(f). 

Many nitrogen-containing compounds engage in a proton-transfer equilibrium that is analogous to keto-enol tautomerism ... 

This type of mesomerisin is much more important in enamines possessing a tertiary nitrogen atom than in those possessing a secondary nitrogen atom since the latter exist largely in the tautomeric imino form (2). 

As pointed out in the introduction, if one of the substituents on the nitrogen atom is a hydrogen atom, tautomeric equilibrium between enamino and imino forms strongly favors the latter form 18,140,141). According to physiochemical measurements, the occurrence of simply substituted /1 -pyrrolines and zl -piperideines is very improbable. The formulation of this type of compound with a double bond in the position (used mainly by early authors) was of formal meaning only, having no experimental evidence (142-144). 

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

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