Solvation energy, tautomerism

A linear solvation energy relationship (LSER) study of tautomerism in aromatic Schiff bases and related azo compounds indicates that the aminoenone tautomer is always the more polar, and is specifically favoured by proton donor solvents (binding to the second lone pair of the carbonyl). Effects of aromatization and benzo fusion are also discussed.26... 

A thione-thiol structure in the crystalline state and in aprotic solvents was established for the [l,2,4]triazolo[3,4- >][l,3,4]thiadiazole (37), in accordance with calculations of the 7r-bonding and solvation energies by the Pariser-Parr-Pople (PPP) method and also on the basis of IR and UV spectral information (75CHE304). The electron-density distribution in four tautomeric forms, calculated by the PPP method, also indicates that the ring-junction carbon atom is the most reactive one with respect to nucleophilic attack (75CHE500). 

A short overview of the quantum chemical and statistical physical methods of modelling the solvent effects in condensed disordered media is presented. In particular, the methods for the calculation of the electrostatic, dispersion and cavity formation contributions to the solvation energy of electroneutral solutes are considered. The calculated solvation free energies, proceeding from different geometrical shapes for the solute cavity are compared with the experimental data. The self-consistent reaction field theory has been used for a correct prediction of the tautomeric equilibrium constant of acetylacetone in different dielectric media,. Finally, solvent effects on the molecular geometry and charge distribution in condensed media are discussed. 

In order to be able to evaluate the model itself, we shall examine a very simple case in which there is only one reactant and one product, having roughly the same molecular volume and the same polarizability in order to neglect the cavitation and dispersion contributions to the variation of the solvation free energy. Tautomeric equilibria offer us a good example of such systems. 

The available quantitative data for the tautomeric constants of 4 and 5 in various solvents [44] allow a detailed elucidation of the solvent effect seen. Using the tools of linear solvation energy relationship theory (see Chapter 11), it was possible to find the share of the open and closed enol tautomers in a given solvent At room temperature, in ethanol, the tautomeric mixture consists 38% a, 15% b, and 47% b in the case of 4, while, in conformity with observed spectral changes, no 5b is present at all. 

For free energies of solvation AGj = AGg, if furthermore the solutes are rigid (no internal degrees of the solute are sampled), then AGg = 0 and the difference in solvation energies between the two tautomeric species is obtained as AGg — = AG2. To obtain AG2, the transformation between the two... 

Free energy perturbation (FEP) theory is now widely used as a tool in computational chemistry and biochemistry [91]. It has been applied to detennine differences in the free energies of solvation of two solutes, free energy differences in confonnational or tautomeric fonns of the same solute by mutating one molecule or fonn into the other. Figure A2.3.20 illustrates this for the mutation of CFt OFl CFt CFt [92]. 

The second aspect is more fundamental. It is related to the very nature of chemistry (quantum chemistry is physics). Chemistry deals with fuzzy objects, like solvent or substituent effects, that are of paramount importance in tautomerism. These effects can be modeled using LFER (Linear Free Energy Relationships), like the famous Hammett and Taft equations, with considerable success. Quantum calculations apply to individual molecules and perturbations remain relatively difficult to consider (an exception is general solvation using an Onsager-type approach). However, preliminary attempts have been made to treat families of compounds in a variational way [81AQ(C)105]. 

A theoretical ab initio study of the gas-phase basicities of methyldiazoles (90JA1303) included a discussion of the 4(5)-methylimidazole tautomer-ism. The RHF/4-31G calculations led to the conclusion that the 4-methyl tautomeric form 14a (R = Me, R = R = H) is 5.2 kJ moP more stable than its 5-methyl counterpart 14b. It was emphasized that this result is to be considered as basic-set dependent. However, a recent theoretical study [94JST(T)45] showed that, starting from the RHF/6-31G level, all the more accurate approximations indicate a higher intrinsic stability for the 4-methyl tautomer. At the MP2/6-31G level, the total energy of the 4-methyl tautomer is 0.7 kJ mol lower than that of the 5-methyl tautomer. Inclusion of solvation effects can, thus, strongly affect the position of the tautomeric equilibrium 14a 14b. Recently, a systematic theoretical study... 

Although the tautomeric ratios of the 4 species have not been measured directly, it is known that in aqueous solution the keto-N2H form dominates, while the keto-NlH form is only detectable in non-polar solvents. An analysis of experimental data concluded that in aqueous solution the stability (lowest free energy) is in the order keto-N2H > imino-N2H > enol-NlH > keto-NIH. In the gas phase, calculations predict that the keto-N2H form is the least stable. While solvation is found to favour this species, which is the most polar, this stabilisation is not enough to reverse the order of stability. It is thus clearly predicted that the keto-NIH tautomer is the most stable in... 

Finally, Nagaoka et al have made a very interesting study applying MC-FEP techniques to the vinyl alcohol - acetaldehyde tautomerism.32 Using a cluster of the solute with three water molecules as a solute , the free energy for the tautomerism was calculated along different reaction pathways, which had been previously found by ab initio calculations including an SCRF solvation term. They were able to deduce that a two-step mechanism is favoured over a concerted one for the transfer of the proton. 

The present chapter thus provides an overview of the current status of continuum models of solvation. We review available continuum models and computational techniques implementing such models for both electrostatic and non-electrostatic components of the free energy of solvation. We then consider a number of case studies, with particular focus on the prediction of heterocyclic tautomeric equilibria. In the discussion of the latter we center attention on the subtleties of actual chemical systems and some of the dangers of applying continuum models uncritically. We hope the reader will emerge with a balanced appreciation of the power and limitations of these methods. 

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A, radius to study tautomeric equilibria in the 3-hydroxyisoxazole system (the keto tautomer 13 is referred to as an isoxazolone). AMI predicts 13 to be 0.06 kcal/mol lower in energy than 14 in the gas phase. However, the AMI dipole moments are 3.32 and 4.21 D for 13 and 14, respectively. Hydroxy tautomer 14 is better solvated within the D02 model, and is predicted to be 2.6 kcal/mol lower in energy than 13 in a continuum dielectric with e = 78.4. Karelson et al. note, however, that the relative increase in dipole moment upon solvation is larger for 13 than for 14 (aqueous AMI dipole moments of 5.05 and 5.39 D, respectively). This indicates that the relative magnitude of gas-phase dipole moments will not always be indicative of which tautomer will be better solvated within a DO solvation approach — the polarizability of the solutes must also be considered. In any case, the D02 model is consistent with the experimental observation [266] of only the hydroxy tautomer in aqueous solution. 

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A radius to study tautomeric equilibria in the 4-hydroxyisoxazole system (they did not specify which hydroxyl rotamer they examined). Tautomer 17 predominates in aqueous solution. Although AMI predicts 16 to be about 10 kcal/mol more stable in the gas-phase than 17, its dipole moment is only predicted to be 0.68 D. Tautomer 17 has a predicted dipole moment of 2.83 D in the gas-phase. With the small cavity, the two dipole moments increase to 0.90 and 4.56 D, respectively, and this is sufficient to make 17 0.3 kcal/mol more stable than 16 in solution. Zwitterion 18 is much better solvated than either of the other two tautomers, but AMI predicts its gas-phase relative energy to be so high that it plays no equilibrium role in either the gas phase of solution. 

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A radius to study tautomeric equilibria in the 2-, 4-, and 5-hydroxyoxazole systems (the keto tautomers are referred to as oxazolones). Tautomers illustrated above in parentheses were not considered and hydroxyl rotamers were not specified. In the first two systems, tautomers 22 and 25 are predicted by AMI to be about 14 kcal/mol more stable than the nearest other tautomer in their respective equilibria. Differences in tautomer solvation free energies do not overcome this gas-phase preference in either case, and the oxazolones are predicted to dominate the aqueous equilibrium, as is observed experimentally [266],... 

The 2-substituted system has proven especially attractive to modelers because the experimental equilibrium constants are known both in the gas phase and in many different solutions. As a result, the focus of the modeling study can be on the straightforward calculation of the differential solvation free energy of the two tautomers, without any requirement to first accurately calculate the relative tautomeric free energies in the gas phase. However, in 1992 Les et al. [290] suggested that prior experimental data [240,266,288], primarily in the form of ultraviolet spectra in the gas phase and in low-temperature matrices, had been misinterpreted and that the reported equilibrium constants referred to homomeric dimers of tautomers (i.e., (42)2 (43)2). Parchment et al. [291] contested this... 

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