Tautomer equilibrium

Contributions in this section are important because they provide structural information (geometries, dipole moments, and rotational constants) of individual tautomers in the gas phase. The molecular structure and tautomer equilibrium of 1,2,3-triazole (20) has been determined by MW spectroscopy [88ACSA(A)500].This case is paradigmatic since it illustrates one of the limitations of this technique the sensitivity depends on the dipole moment and compounds without a permanent dipole are invisible for MW. In the case of 1,2,3-triazole, the dipole moments are 4.38 and 0.218 D for 20b and 20a, respectively. Hence the signals for 20a are very weak. Nevertheless, the relative abundance of the tautomers, estimated from intensity measurements, is 20b/20a 1 1000 at room temperature. The structural refinement of 20a was carried out based upon the electron diffraction data (Section V,D,4). 

The very same philosophy can also be applied to metal complexes. Indeed, metal compounds containing methylated nucleobases [e.g., 1,9-dimethylguanine (1,9-DiMeG) (258), 7,9-DiMeG (131a, 259), 6,9-DiMeG (258), 1,9-DiMeA (260), 6,9-DiMeA (52), or 6,6,9-trimethylguanine (6,6,9-TriMeA) (53)] have been reported, but only in one case has the effect of metal ion coordination on the tautomer equilibrium of a nucleobase (adenine) been measured (52). 

In the solid state, 4(5)-nitro-5(4)-methoxyimidazole exists as a 1 1 mixture of the two prototropic annular tautomers <2004AXB191>. However, in histidine-dipeptides, the tautomer equilibrium (N -H vs. N -H) has been found to vary depending on the nature of the peptide structures <2005JA12544>. 

As expected, there are no signs of a tautomer equilibrium between l,4,2-oxathiazin-6(57/)-ones 5 and the formally antiaromatic 6-hydroxy derivatives 6.46... 

Comparison of their electronic parameters indicates that there is a correlation between the biological activity under consideration and the tautomer equilibrium. The larger the positive charge on the hydrogen atoms at the nitrogens in the heterocycle and the closer the Cs Cg bond order to 1.5, the easier the transformation 62 63 ... 

Two more binding possibilities - via one of the exocyclic oxygens (27,28) or with replacement of the proton at C5 (29,30) will not be considered here, since they occur with the neutral ligands and do not involve the N1,N3 tautomer equilibrium of the monoanionic ligands, respectively. 

To address the shortcomings in FEP results, Worth and Richards used their previously studied system of histamine monocation in aqueous solution and calculated the corresponding tautomer equilibrium constant. The intra-and intermolecular contributions to the relative SFE were evaluated separately ... 

In 2008 Ai published a study (Ai et al. 2008) on tautomer equilibrium of adenine in the presence of Zn cation at the DPT level (B3LYP/6-311+G ). It was foimd that the [Zn-(Ade-N6,N7)] imino complex is the most stable structure in accord with the gas phase calculations of Kabelac (Kabelac and Hobza 2006). The latter calculations explored tautomers of all DNA bases in the presence of Na, Mg, and Zn bare cations evaluated at the R1-MP2/TZVPP level of theory. 

The tautomer equilibrium of a few perfluorallg l/aryl substituted secondary phosphine oxides synthesized via the Y-P(C2Fs)(NEt2) (where... 

The mass-spectrometric fragmentation of 2-aminothiazole-3-oxides is characterized by the abstraction of O and OH out of the molecule ion. Variations observed in the mass spectra suggest an equilibrium between tautomers 354a and 354b in the gas phase (Scheme 203). 

Since polar solvents would be expected to stabilize polar forms, a retreat towards the hydroxy tautomer (71) would be predicted in solvents less polar than water, and in the vapour phase. This is borne out in practice at equilibrium both 2- and 4-hydroxypyridine (as well as the 3-hydroxy compound, which even in water exists as an approximate 1 1 mixture of OH and NH forms) exist as such, rather than as the pyridinones. However, the 2- and 4-quinolinones remain in the NH (keto) forms, even in the vapour phase. Hydrocarbon or other solvents of very low polarity would be expected to give results similar to those in the vapour phase, but intermolecular association by hydrogen bonding often leads to a considerably greater proportion of polar tautomers being present than would otherwise have been predicted (77ACR186, 78JOC177). 

The comparison of the experimental mean values with the theoretically calculated ones for individual tautomers (Section 4.04.1.5.1) (76AHC(S1)1) or conformers (Section 4.04.1.4.3) has been used in the literature to determine equilibrium constants. Thus, the experimental value for l,l -thiocarbonylbis(pyrazole) (40) is 3.19 D and the vector sums of the simple group moments after addition of the extra mesomeric moments are shown in Figure 8. From these values Carlsson and Sandstrom (6SACS1655) concluded that conformation (40b) exerts the largest influence. 

The last example is somewhat more complicated since four isomers (two tautomers and two conformations) are present at equilibrium (Figure 9) (78BSB189). The experimental value (3.73 D, Table 3) establishes the predominance of the 3-azido tautomer but does not allow the determination of the conformational equilibrium other methods (Section 4.04.2.3.4(v)) are necessary to establish definitely the Z conformation (43b). 

The mean chemical shifts of A- unsubstituted pyrazoles have been used to determine the tautomeric equilibrium constant, but the method often leads to erroneous conclusions (76AHC(Sl)l) unless the equilibrium has been slowed down sufficiently to observe the signals of individual tautomers (Section 4.04.1.5.1). When acetone is used as solvent it is necessary to bear in mind the possibility (depending on the acidity of the pyrazole and the temperature) of observing the signals of the 1 1 adduct (55) whose formation is thermodynamically favoured by lowering the solution temperature (79MI40407). A similar phenomenon is observed when SO2 is used as solvent. 

All the N-unsubstituted pyrazoles (129) in solution (and probably in the gas phase) are mixtures of annular tautomers in different proportions, depending on the nature of the substituents R and R. In the majority of cases the difference of free energy between both tautomers is low enough for the chemical reactivity to be unrelated to the equilibrium constant. 

When R = H, in all the known examples, the 3-substituted tautomer (129a) predominates, with the possible exception of 3(5)-methylpyrazole (R = Me, R = H) in which the 5-methyl tautomer slightly predominates in HMPT solution at -17 °C (54%) (77JOC659) (Section 4.04.1.3.4). For the general case when R = or a dependence of the form logjRTT = <2 Za.s cTi + b Xa.s (Tr, with a>0,b <0 and a> b, has been proposed for solutions in dipolar aprotic solvents (790MR( 12)587). The equation predicts that the 5-trimethylsilyl tautomer is more stable than the 3-trimethylsilylpyrazole, since experimental work has to be done to understand the influence of the substituents on the equilibrium constant which is solvent dependent (78T2259). There is no problem with indazole since the IH tautomer is always the more stable (83H(20)1713). 

Together with pyridones, the tautomerism of pyrazolones has been studied most intensely and serves as a model for other work on tautomerism (76AHC(Sl)l). 1-Substituted pyrazolin-5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), (DH (78b) and NH (78c). In the vapour phase the CH tautomer predominates and in the solid state there is a strongly H-bonded mixture of OH and HN tautomers (Section 4.04.1.3.1). However, most studies of the tautomerism of pyrazolones correspond to the determination of equilibrium constants in solution (see Figure 20). 

Hydrogen bonding plays a major role in pyrazolone tautomerism, and the formation of a chelate structure can shift the equilibrium towards the chelated form. Structures (135) and (136) are two representative examples of such stabilized tautomers. Structure (137) is a hypothetical example of stabilization of the NH tautomer. 

The problem of tautomerism is simpler in the case of 1-substituted pyrazolin-3-ones since only two forms, the OH (140a) and the NH (140b), are possible. The OH form is the more stable and is the only one present in the crystal (Section 4.04.1.3.1). In protic solvents, like water or methanol, the equilibrium position is much more evenly balanced between the OH and NH forms. Finally, 4-hydroxypyrazoles (141) exist as such. A CNDO/2 calculation justifies the result that 4-hydroxy tautomers are relatively more stable than... 

In the case of 4-hydroxypyrazole, tautomer (159), although not abundant in the equilibrium mixture (Section 4.04.1.5.2), must be considered when discussing their reactivity. 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

Analogously, pyrazolyl-aluminate and -indate ligands have been prepared <75JCS(D)749) and their chelating properties evaluated with cobalt, nickel, copper and zinc. Gallyl derivatives of pyrazoles and indazoles have been extensively studied by Storr and Trotter e.g. 75CJC2944) who determined several X-ray structures of these compounds. These derivatives exist in the solid state as dimers, such as (212) and (288). A NMR study in acetone solution showed the existence of a slow equilibrium between the dimer (212) and two identical tautomers (289) and (290) (Section 4.04.1.5.1) (81JOM(215)157). 

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