Tautomeric lactam/lactim

The lactam-lactim tautomerism of hydroxyquinazolines is reflected in their chemical reactivity. Thus they are chlorinated to 4-chloro-quinazolines (see Section VI,A), and both 0- and A-methylation have been observed. When a substituent is already present on a nitrogen atom, as in 3-methyl-4(3i7)quinazolinone, chlorination gives 4-chloroquinazoline with loss of the methyl group (see la). 2-... 

Similar considerations apply to nitrogen-containing heterocycles carrying acidic groups, for example 2-hydroxypteridine, but the situation is further complicated by lactam-lactim tautomerism in the neutral species. Thus, hydroxypteridines exist predominantly as lactams, such as 6, in dynamic equilibrium with small amounts of lactims, such as 7. There is, in consequence, a decrease in the aromatic... 

Solutions of the violet photoproduct (CLI) in ethyl benzoate show reversible thermochromic changes attributed to reversible changes (lactam-lactim tautomerism) (CLI CLII).251... 

A number of 3(2//)-isoquinolinone derivatives (8) have been synthesized by De k and his research group (Section II,B,3) to make possible a general evaluation of their lactam-lactim tautomerism [84ACH( 116)303 89ACH869]. 

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). 

The shifts of the tautomeric equilibria (lactam —> lactim, amine -> imine, or thione -> thiol) in N-heterocyclic molecules caused by substituents are of considerable interest. Several such studies are available for cytosines. 

It was generally conceded139-179 that glycosylation at N1 of the pyrimidine ring is not a feasible approach where lactam-lactim tautomerism of the OH OH... 

The lactam-lactim, tautomerism, of hydroxypurines illustrated, for example, for hypoxanthine by the structures 8 and 9. 

The amine-imine and the lactam-lactim tautomerisms may, of course, be coupled with the shift of the imidazole proton on the purine skeleton. In polysubstituted derivatives, e.g., in 8-azaguanine, all the different types of tautomerisms may be intermingled. 

O-H bond. Among such properties a prominent one is the ultraviolet absorption spectrum and the theory may therefore be used for the examination of some of the spectroscopic shifts which accompany the lactam-lactim tautomerization. Much caution must, however, be exercised in this respect. Thus, in a recent paper Kwiatkowski135,137 performed Pariser-Parr-Pople-type calculations on the electronic structure of hydroxypurines, essentially to interpret their ultraviolet spectra. In these calculations he assumed that these compounds exist predominantly in their lactim form, and the results of his calculations, at least for 6- and 8-hydroxypurine, did not seem to contradict this assumption. It is only in the case of the 2-hydroxy isomer that a particularly striking disagreement between theory and experiment led him to admit that this last compound may exist in the lactam form. Calculations carried out for this form gave, in fact, a more satisfactory agreement with experiment.138 As we have seen, unambiguous infrared spectroscopy evidence clearly show s that all three isomers exist essentially in the lactam form. This shows that ultraviolet absorption may provide only very uncertain evidence about the lactam-lactim tautomerism in hydroxypurines and related compounds. 

This precaution stated, a simultaneous theoretical investigation of the essential spectroscopic features of the lactam and lactim forms of the three fundamental monohydroxypurines yields some interesting results. These are summarized in Table XII, together with the corresponding experimental data, which in the case of lactim forms refer to the methoxy derivatives. As in all these compounds there is besides the lactam-lactim tautomerism, the possibility of an oscillation of the imidazole proton between the different N atoms of the ring system, Table XII indicates the exact tautomeric form or forms to which the calculations refer. In case of the lactam forms these are the most probable tautomers of such forms obtained in the study described in the next section. For the lactim forms they are the a priori most probable ones. 

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... 

Where lactam-lactim tautomerism exists, the lactam form is usually considered to predominate as a result of work on other systems (63AHC(2)1, 50HCA273). 

Note that the shape of the absorption spectra of phenoxynaphthacenepyridones depended on the solvent, which is assignable to the lactame-lactime tautomerism. In this case, the equilibrium position depended on the solvent nature. Polar solvents shifted the equilibrium to the lactime form. 

Fig. 1 (a) Lactam/lactim prototropic tautomerization (b) displacement of a Pt center on a stilbazole... 

Instead of 2,4-dialkopyrimidines, some other alkoxy heterocyclics capable of lactam-lactim tautomerism were used, e.g., 2-ethoxy-pyridine42,43 (36), 4-ethoxypyridine44 (37), and 3,6-dibenzyloxy-pyridazine45 (38). Treatment of a-acetobromoglucose with 36 gave... 

The tautomeric 6-hydroxy-7-azaindole shows a shift to longer wavelength, which is characteristic of 2-hydroxypyridine as the neutral molecule or of l-methyl-2-pyridone. The degree of tauto-merization is solvent-dependent, and Yakhontov et have determined the lactam/lactim R = Me) ratio from the position of... 

There are various forms of tautomerism which operate in the different purine species. (1) Prototropy which involves attachment of the proton to any one of the four ring nitrogen atoms (Scheme 5). Corresponding CH tautomers, for example (52), seem to be of little significance. (2) Amine-imine tautomerism which operates in the aminopurines such as adenine (Scheme 6). (3) Lactam-lactim tautomerism as in the hydroxypurines such as hypoxanthine (Scheme 7) and the related thioxo-thiol tautomerism (53) and (54) in the biologically imporfant mercaptopurines (Scheme 8). The subject has recently been discussed in some detail <76AHC(Si)502>. 

AHOMO and ALUMO are not very different from each other, the same procedure can be applied to such compounds in order to gain information about the protonation site, for example, in the various aza analogues of indolizine (10), or about the tautomerism in heterocycles as exemplified by the lactam-lactim isomerism in 2-pyridone (11) and about positional isomerism such as in the tautomeric 3,5- and 3,6-diazaindoles (12, 13). This is possible since the protonation of a nitrogen or the replacement of a carbon by a heteroatom can be viewed as a special case of substitution. 

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