N-hydroxy-, tautomers

The reliability of semi-empirical methods (AMI, PM3, and MNDO) for the treatment of tautomeric equilibria has been tested for a series of five-membered nitrogen heterocycles, including 1,2,3-triazole and benzotriazole. The known tendency of MNDO to overestimate the stability of heterocycles with two or more adjacent pyridine-like lone pairs is also present in AMI and to a somewhat lesser extent in PM3. Tautomers with a different number of adjacent pyridine-like nitrogens cannot be adequately treated by these semi-empirical methods. Both AMI and PM3 represent major improvements over MNDO in the case of lactam-lactim tautomerism. The stability of N-oxides as compared to N-hydroxy tautomers is overestimated by PM3 method. All three methods give reliable ionization potentials and dipole moments (90ZN(A)1328). 

Af-Oxidation is very sensitive to steric effects, since 1-substituted lumazines and pterins give only 5-oxides and the presence of bulky substituents at position 7 also directs oxidation to N-5. The pteridine 5-oxide (52) and 8-oxide (53) and the 5,8-dioxide (55) contain the N-oxide groups as such, even when the possibility of N-hydroxy tautomers exists, as in... 

For most simple phenols this equilibrium lies well to the side of the phenol, since only on that side is there aromaticity. For phenol itself, there is no evidence for the existence of the keto form. However, the keto form becomes important and may predominate (1) where certain groups, such as a second OH group or an N=0 group, are present (2) in systems of fused aromatic rings and (3) in heterocyclic systems. In many heterocyclic compounds in the liquid phase or in solution, the keto form is more stable, although in the vapor phase the positions of many of these equilibria are reversed. For example, in the equilibrium between 4-pyridone (118) and 4-hydroxypyridine (119), 118 is the only form detectable in ethanolic solution, while 119 predominates in the vapor phase. " In other heterocycles, the hydroxy-form predominates. 2-Hydroxypyridone (120) and pyridone-2-thiol (122) are in equilibrium with their tautomers, 121 and 123, respectively. In both cases, the most stable form is the hydroxy tautomer, 120 and 122. ... 

One representative of the oxazolo[4,5-/][ 1,6]naphthyridine system, viz. the ester 62, is produced in four steps by annulation of 2-(dicthy lam ino)oxazolo[4,5- pyridine (Scheme 20). Whether the final product exists mainly as the hydroxy tautomer or as the 9//-6-one cannot be deduced from the spectral data presented alkylation occurs either at the oxygen or at N-9, and gives either 63 or 64 <1993SC2931>. 

At low enough temperatures vibrational fine structure of aromatic chromophores may be well resolved, especially if they are embedded in a suitable matrix such as argon or N2, which is deposited on a transparent surface at 15 K. This matrix isolation spectroscopy77166 may reveal differences in spectra of conformers or, as in Fig. 23-16, of tautomers. In the latter example the IR spectra of the well-known amino-oxo and amino-hydroxy tautomers of cytosine can both be seen in the matrix isolation IR spectrum. Figure 23-16 is an IR spectrum, but at low temperatures electronic absorption spectra may display sharp vibrational structure. For example, aromatic hydrocarbons dissolved in n-heptane or n-octane and frozen often have absorption spectra, and therefore fluorescence excitation spectra, which often consist of very narrow lines. A laser can be tuned to excite only one line in the absorption spectrum. For example, in the spectrum of the carcinogen ll-methylbenz(a)anthrene in frozen octane three major transitions arise because there are three different environments for the molecule. Excitation of these lines separately yields distinctly different emission spectra.77 Likewise, in complex mixtures of different hydrocarbons emission can be excited from each one at will and can be used for estimation of amounts. Other related methods of energy-... 

Below pH 6,2-pyridone (19) is brominated in aqueous solution as the neutral species, preferentially in the 3-position. Above pH 6, the conjugate anion (20) is brominated mainly at C-5. At low pH, the hydroxy tautomer (21) has been shown to be at least 2000 times less reactive than 19. N-Methylpyridones are not particularly reactive above pH 6 because they cannot form the anions. The 5-bromo derivatives of 19 behave similarly except that 5-bromo-2-pyridone is much more reactive than its /V-methyl derivative above pH 4. This is in accord with the lower pKa value of the bromo compound [82JA4142 90AHC(47)303] (Scheme 16). 

Nitrobenzimidazole-2-carboxylate 3-oxides on X-ray diffraction data exist in /V-hydroxy tautomers [190], In the crystal a strong 0-(HN)-N-.,.intermolecular bond gives rise to supramolecular polymeric chains in the lattice. 

A comparison of the tautomeric constants in the series of N -substituted cytosines indicates an interesting trend. As seen above, in the case of cytosine itself, the ratio of the tautomers of the amine type 2 to those of the imine type 6 is about 10 . In the case of A ramino-cytosine the amine form 22 predominates by a factor of about 30, while N -hydroxy compounds have mainly the imine form 21 with tautomeric constant 10 [i.e., Kf (amine/imine) = 10 ]. Another study of this constant gave the value of 25 K (amine/imine) = 4 X 10 ] in favor of the imine. 

Fig. 6. Net total electronic charges in N -amino and N -hydroxy substiliuted cytosine tautomers calculated by the CNDO/2 method. The numbers in parentheses indicate n -charges.

C-Hydroxy-8-azapurines do not exist as such but as equilibrium mixtures (e.g., 8 9) in which the cyclic amide tautomers greatly preponderate over the hydroxy tautomer. This behavior parallels what was found in the pyridine, pyrimidine, and purine series on evidence from ionization constants and the UV spectra of C- and A -methyl derivatives. A formal name for9 is 1,6-dihydro-8-azapurin-6-one but such specification of the hydrogen atom s position is, in the absence of data, risky for example, pyrimidin-4-one is an equilibrium mixture in which tautomers with mobile hydrogen on N-3 and N-1 preponderate in a 5 2 ratio, respectively. Hence the simpler names, such as 8-azapurin-6-one, will be used in this review. 

Tautomerism of 2,1,3-benzothiadiazinone 2,2,-dioxide 63 and its N-monosubsti-tuted derivatives has been studied experimentally by 3H and 13C NMR and theoretically by ab initio calculations. In the gas phase, the oxo form 63b was found to be more stable (AE — 4-6 kcal/mol) than the hydroxy form 63a however, due to the higher dipole moment of the latter this energy difference is greatly decreased in solution. Whereas both tautomers 63a and 63b were observed in non-polar solvents (THF) and protic solvents (methanol), only hydroxy tautomer 63a was detected in polar aprotic solvents (DMSO-<76) and in the solid state. The tautomerism is also present in the N-monosubstituted derivatives of 63, which exist primarily as oxo tautomers (99T12405). 

Molecular orbital CNDO/2 studies of 2,6-diamino-4-hydroxypyrimidine and 2-amino-4-hydroxyquinazoline predicted that in both cases the aromatic amino-hydroxy tautomer is the most stable. Of the other tautomers, N(lH)-oxo form is more stable than N(3H)-oxo form for 2,6-diamino-4-hydroxypyrimidine, whereas the opposite trend is calculated for 2-amino-4-hydroxyquinazoline (85IJQC(28)315). 

Diethyl methyloxalacetate (106J, R = Me) adds to tetrahydropyridine and forms a new pyrroledione ring, but diethyl oxalacetate gives a product which is shown to be the enol form of the corresponding dione [2744]. The 1,2-double bond of 3A/-indoles undergoes a cycloaddition on treatment at ambient temperature with either diethyl oxalacetate or oxalopropionate. When R = H, the product may exist as its 2-hydroxy tautomer [3394]. Successive N- and... 

Studies on the tautomeric equilibria of 3,5-diamino-4-hydroxyimino-l,2,6-thiadiazine 1,1-dioxides (79 R = H) and 5-amino-4-hydroxyimino-1,2,6-thiadiazin-3(2//)-one 1,1-dioxides (80) are also available <88Mi 6i6-oi>. On the basis of H, C, and N NMR studies it is concluded that in all instances, the oxime tautomers are preferred over the 4-nitroso- forms, and that the 3-ones exist as the lactams rather than the 3-hydroxy tautomers. In addition, for the diamino-oxime (79 R = H) and its 0-methyl ether (79 R = Me), the amino rather than the imino tautomer is dominant. In contrast, with the 5-amino-1,2,6-thiadiazinone 1,1-dioxides (80 R = H or PhCHj) there appear to be unquantified amounts of the imino tautomers (81) present. 

Identified (noted as the hydroxy tautomer) only by mass spectroscopy by Andrade-Aispuro and Crouzet (1983) in the volatile compounds emitted during roasting (see N.20). 

The gas-phase equilibrium between 2-hydroxypyridine and 2-pyridone favours the hydroxy-form, but in the equilibrium between 2-hydroxypyridine iV-oxide and N-hydroxy-2-pyridone, the major tautomer is the hydroxy-pyridone. Bicyclic adducts between 2-pyridones and dimethyl acetylene-dicarboxylate, unobtainable at atmospheric pressure, have been obtained at 10—15 kbar. A novel route to iV-hydroxy-2-pyridone involves the trimethyl-silylation of 2-pyridone followed by oxidation of the resulting 2-(trimethyl-silyloxy)pyridine with the DMF complex of molybdenum pentoxide. p-Nitro-phenols (45) and nitro-acetamides (46) are formed from the reaction of 3,5-dinitro-2-pyridones (43) with the sodium salts of /3-keto-esters (44) (Scheme 20). ... 

The benzotriazinones 3 will be treated among the fully conjugated systems in this chapter, because the 4-hydroxy tautomer and the delocalized anion are fully conjugated, and it would mean an undue fragmentation of the material to be covered if, for reasons of nomenclature usage, at N-3 substituted compounds 3, which cannot form 4-hydroxy tautomers, were to be treated separately. Related considerations apply for the systems 4 and 5. 

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