Lactim-lactam tautomers

Hydroxypyrazino[2,3-r/]pyridazin-5(6//)-one exists predominantly as the lactim-lactam tautomer 162 in aqueous solution (79AJC459).This conclusion was supported by semiempirical calculations (AMI method) of the relative energies for the dilactam, dilactim, and lactim-lactam tautomers (91JCC17). The UV spectroscopy studies and pK values for 162 and its N-and <7-methyl derivatives suggest that monoprotonation occurs in the pyrazine ring. 

Acylation of l,2,4-triazolo[l,5-c]quiiiazoliii-5-oiie (141) with ethyl chlo-roformate occurred at N6 to afford the 6-ethoxycarboiiyl derivative 142 (75CB3799) (Scheme 55). Tliis result indicates that the amide tautomer (lactam tautomer) 141 prevailed over the corresponding imidic acid tautomer (lactim tautomer). 

Tlie infrared spectra revealed the dominance of the 2-oxo (153) and 5-0X0 (157) structures (amide or lactam tautomers) over the 2-hydroxy (154) and the 5-hydroxy (192) structures (imidic acid or lactim tautomers)... 

In the case of the 4-chloro-l-phenyl derivative (6) (88S683), more data support the lactim structure. The UV spectrum of 7 (76JMC395) in water has only the lactam band, whereas in diethyl ether, only the lactim structure is shown. In ethanol, the lactam tautomer predominates, but in chloroform, the lactim tautomer predominates. 

In the isoquinolinones annellated with a benzene ring at the [/] and [/ ] stites, the lactam tautomer predominates, except for the benzo[g]iso-quinolinone (9), which exists in the lactim form [89JCR(S)340] similar to the 1,4-diphenyl derivatives [72JCS(P1)2722]. Cyclopenta[/]-isoquinoli-none is present exclusively in the lactam form in both water and 95% alcohol (75JMC399). 

Whatever be the difficulties in dealing satisfactorily with the problem of the lactam-lactim tautomerism in hydroxypurines, the predominance of the lactam tautomer granted, there remains the problem of the detailed structure of the most probable lactam form for each isomer. The problem is essentially that of the site of location of the imidazole proton. From that point of view forms 34-38 have to be considered for 2-hydroxypurine, forms 39—42 for 6-hydroxypurine (hypoxanthine), and forms 43-45 for 8-hydroxypurine. There are, in addition, some betaine tautomeric forms but these are probably of low stability and will not be considered further. Before describing the results of theoretical calculations, it may be useful to indicate that from the experimental point of view we may, in this respect, turn again for significant evidence to infrared spectroscopy... 

For the corresponding l//-2-hydroxypyrrolo[2,3-c]pyridine isomer, a mixture of both lactam and lactim forms has been observed in solution as well as in the crystalline state. It is interesting to note that the lactam tautomer predominates for l//-2-hydroxy-3-ethoxycarbonylpyrrolo[2,3-c]pyridine, whereas the lactim form is the major tautomer for the corresponding pyrrolo[3,2-6]pyridine derivative <74JCS(P1)1531>. Similarly, for 1 //-6-hydroxypyrrolo[2,3-6]pyridine, both lactam and lactim tautomers are present in solution and the crystalline states <66T3233>. For the 2-hydroxy derivative of compound (3), both IR and H NMR spectroscopy indicate that approximately equal amounts of the alcohol and carboxyl derivative are present <77CHE1224). 

The lactim/lactam tautomerism of hydroxamic acids and their O-alkyl and O-acyl derivatives has also been studied [146], Hydroxamic acids exist in the solid state and in polar solvents as the lactam tautomer only, whereas in nonpolar solvents the hydroximic tautomer is also present. Further analogous solvent-dependent lactim/lactam equilibria have been observed for certain Schiff bases (prepared from anilines and 2(4)-hydroxybenzaldehyde [256] or 2-hydroxynaphthaldehyde [257]), for 3-hydroxypyrazole [258], and for 3-methyl-l-phenylpyrazolin-5-one [259]. 

As far as we are aware, this type of calculation has been performed for lactim and lactam tautomers of both 2- and 4-oxopyridines [(2), (3)] and for formamide (6a) and formimidic acid (6b) only (Schlegel et al., 1982 Scanlan et al., 1983). Since the calculations mentioned are expensive, one estimates the S a b,> value by comparison of the electronic energies calculated in the HF approximation only [(HF)8EAliq)L and even this has often been done by means of semiempirical methods [(CNDO/2i8 A B,... 

Thermodynamic Quantities and Relative Electronic Energies 8 jq) for the Lactim (A) and Lactam (B) Tautomers of 2-Oxopyridine in the Vapor Phase (the Lactam Tautomer Considered as the Reference System)0... 

Both models mentioned have been used to investigate the simultaneous influence of electronic excitation and solvation (hydration) on the tautomeric equilibrium in the first two excited states of 2- and 4-oxopyri-dine tautomers (2a), (2b) and (3a), (3b). The relative stabilization energies A a,b( ) in the first two excited electronic states of the tautomers in question are given with the available experimental data in Table VIII. Comparison with experimental data can only be done for the second excited state (the appropriate experimental data for the first n - 7r state are not available). In the case of 2-oxopyridine the value of Af2a,2b( ) is estimated to be equal to -(5.4-11.7) kJ mole-1 from shifts of the absorption bands of the lactim and lactam tautomers of 2-oxopyridine and the... 

IR and UV absorption spectroscopy of 6-chloro-2( 1 //j-pyridone acetic acid mixtures in carbon tetrachloride at room temperature indicated lactim-acid and lactam-acid heterodimer formations, preferential association being with the lactam tautomer. In the presence of acetic acid, the proportions of monomeric pyridone species diminish (80JCS(P2)620). 

Lactam (kcto tautomer) Lactim (cnol tautomer)... 

The lactim-lactam phototautomerization was studied by means of 2-(6 -hydroxy-2 -pyridyl)benzimidazolium in water [61]. It was found that two pathways exist, namely, a water-assisted proton translocation by probably a double proton transfer, and a two-step process during which the molecule dissodates and forms a zwitteri-onic species which is protonated at the pyridine nitrogen. The disappearance of the lactim tautomer after optical excitation takes less than 1 ns, while the zwitterionic form and the lactam tautomer have an exdted-state Hfetime of a few nanoseconds. Studies on 5-(4-fluorophenyl)-2-hydroxypyridine revealed that, after optical excitation of the lactim form, a tautomeric equiHbrium is established by proton transfer processes, again on a subnanosecond timescale [62]. 

The complex annular lactam-lactim tautomerism of a large variety of 7-OH(SH,NH2)-l,2,4-triazolo[l,5-a]pyrimidines 45 (Scheme 5.36) was studied in DMSO-dg by applying NMR spectra because 3( C) values proved to be very similar [85]. For X = 0 and S, only 3- and 4-lactam tautomers 45b,c and for X = NH the lactim tautomer 45a were found. The tautomers were computed with respect to relative energy and chemical shifts at the ah initio MO level. 

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). 

On the basis of UV spectroscopic data of derivatives with fixed lactam and fixed lactim structures, it was established that the bands characteristic of the lactam form appear between 385 and 438 nm, while those characteristic of the lactim form are found in the range 312-360 nm, depending on the substituents (in 95% ethanol). Coumpound 9, in which the bands are shifted to the higher wavelengths because of the linearly annellated benzene ring is an exception. Most of these compounds exist predominantly in 95% alcohol as the lactim tautomer. In compound 8a, the ratio of the... 

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